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Jiang H, Zhang X, Yang W, Li M, Wang G, Luo Q. Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice. Front Pharmacol 2022; 13:869794. [PMID: 35496274 PMCID: PMC9039014 DOI: 10.3389/fphar.2022.869794] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/29/2022] [Indexed: 11/15/2022] Open
Abstract
Background and Aims: Hepatic iron overload always leads to oxidative stress, which has been found to be involved in the progression of liver disease. However, whether iron disorder is involved in acute liver disease and the further molecular mechanisms remain unclear. Methods: A mice model of acute liver injury (ALI) was established via intraperitoneal injection of thioacetamide (TAA) (250 mg/kg/day) for 3 consecutive days. Ferrostatin-1 (Fer-1) was administered intraperitoneally (2.5 μM/kg/day) starting 3 days before TAA treatment. Deferoxamine (DFO) was intraperitoneally injected (200 mg/kg/day) with TAA treatment for 3 days. We further observed the effect of Fer-1 on TAA model with high-iron diet feeding. ALI was confirmed using histological examination and liver function activity. Moreover, expressions of iron metabolism and ferroptosis proteins were measured by Western blot analysis. Results: The study revealed that the iron accumulation and ferroptosis contributed to TAA-induced ALI pathogenesis. TAA induced prominent inflammation and vacuolar degeneration in the liver as well as liver dysfunction. In addition, protein expression of the cystine/glutamate antiporter SLC7A11 (xCT) and glutathione peroxidase 4 (GPX4) was significantly decreased in the liver, while transferrin receptor 1 (TfR1), ferroportin (Fpn) and light chain of ferritin (Ft-L) expression levels were increased after TAA exposure. As the same efficiency as DFO, pre-administration of Fer-1 significantly decreased TAA-induced alterations in the plasma ALT, AST and LDH levels compared with the TAA group. Moreover, both Fer-1 and DFO suppressed TfR1, Fpn and Ft-L protein expression and decreased iron accumulation, but did not affect xCT or GPX4 expression in the liver. Both Fer-1and DFO prevented hepatic ferroptosis by reducing the iron content in the liver. Furthermore, Fer-1 also reduced iron and reversed liver dysfunction under iron overload conditions. Conclusion: These findings indicate a role of TAA-induced iron accumulation and ferroptosis in the pathogenesis of ALI model. The effect of Fer-1 was consistent with that of DFO, which prevented hepatic ferroptosis by reducing the iron content in the liver. Thus, Fer-1 might be a useful reagent to reverse liver dysfunction and decreasing the iron content of the liver may be a potential therapeutic strategy for ALI.
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Affiliation(s)
| | | | | | | | - Guohua Wang
- *Correspondence: Guohua Wang, ; Qianqian Luo,
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Atef Y, El-Fayoumi HM, Abdel-Mottaleb Y, Mahmoud MF. Effect of cardamonin on hepatic ischemia reperfusion induced in rats: Role of nitric oxide. Eur J Pharmacol 2017; 815:446-453. [PMID: 28966130 DOI: 10.1016/j.ejphar.2017.09.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/13/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023]
Abstract
Ischemia reperfusion (I/R) injury is a cellular damage in a hypoxic organ following the restoration of oxygen delivery. It may occur during organ transplantation, trauma and hepatectomies. Nitric oxide (NO) effects during hepatic I/R are complicated. The iNOS-derived NO has a deleterious effect, whereas eNOS-derived NO has a protective effect in liver I/R. Cardamonin (CDN) is an anti-inflammatory molecule and a novel iNOS inhibitor, and Nω-Nitro-L-arginine (L-NNA) is a NOS inhibitor. L-Arginine is a precursor of NOS. This study was designed to investigate the possible protective effects of CDN on hepatic I/R and the role of NO. Wistar rats were randomly divided into 5 groups (Sham, I/R, CDN, L-NNA and L-arginine). Liver ischemia was induced for 45min then reperfusion was allowed for 1h. L-Arginine and CDN ameliorated the deleterious effects of I/R through reducing the oxidative stress and hepatocyte degeneration. Both molecules decreased the elevated inflammatory cytokines and increased the antiapoptotic marker, Bcl2. Both agents increased NO and eNOS expression and decreased iNOS expression. In conclusion, increased NO/eNOS and suppression of iNOS expression have protective effects on I/R injury. While inhibition of eNOS and reduction of NO have deleterious effects on I/R injury. For the first time, we demonstrated that cardamonin improved functional and structural abnormalities of the liver following I/R by improving oxidative stress and inflammation and increasing the availability of NO produced by eNOS. Treatment with cardamonin could be a promising strategy in patients with hepatic I/R injury in different clinical situations.
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Affiliation(s)
- Yara Atef
- Department of Pharmacology & Toxicology & Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Hassan M El-Fayoumi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; Faculty of Pharmacy, Sinai University Qantara, Egypt
| | - Yousra Abdel-Mottaleb
- Department of Pharmacology & Toxicology & Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Reis AS, Pinz MP, Bortolatto CF, Jesse CR, Savegnago L, Roman S, Luchese C, Wilhelm EA. Antioxidant compound (E)-2-benzylidene-4-phenyl-1,3-diselenole protects rats against thioacetamide-induced acute hepatotoxicity. Can J Physiol Pharmacol 2017; 95:1039-1045. [PMID: 28704613 DOI: 10.1139/cjpp-2016-0118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to investigate whether (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) protects against hepatotoxicity induced by thioacetamide (TAA). On the first day of treatment, male adult Wistar rats received BPD (10 or 50 mg·kg-1). On the second day, the rats received a single intraperitoneal injection of TAA (400 mg·kg-1). Twenty-four hours after TAA administration, biochemical determinations and liver histological analysis were carried out. BPD (50 mg·kg-1) reduced plasma aspartate and alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities increased by TAA exposure. Treatment with BPD was effective against increased lipid peroxidation levels and attenuated a decrease in hepatic reduced glutathione and ascorbic acid levels as well as an inhibition of glutathione peroxidase activity caused by TAA exposure. The higher dose of BPD protected against the inhibition of hepatic δ-aminolevulinic dehydratase activity induced by TAA. Finally, histopathological examination of the liver showed that BPD markedly ameliorated TAA-induced hepatic injury. In conclusion, BPD protected against hepatotoxicity and oxidative stress caused by TAA exposure in rats.
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Affiliation(s)
- Angélica S Reis
- a Programa de Pós-graduação em Bioquímica e Bioprospecção (PPGBBio), Grupo de Pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, CEP 96010-900, RS, Brasil
| | - Mikaela P Pinz
- a Programa de Pós-graduação em Bioquímica e Bioprospecção (PPGBBio), Grupo de Pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, CEP 96010-900, RS, Brasil
| | - Cristiani F Bortolatto
- b Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brasil
| | - Cristiano R Jesse
- c Universidade Federal do Pampa, Campus Itaqui, Itaqui, CEP 97650-000, RS, Brasil
| | - Lucielli Savegnago
- a Programa de Pós-graduação em Bioquímica e Bioprospecção (PPGBBio), Grupo de Pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, CEP 96010-900, RS, Brasil
| | - Silvane Roman
- d Universidade Regional Integrada do Alto Uruguai e das Missões Erechim, Fundação Regional Integrada, Ciências da Saúde, Erechim, CEP 99700-000, RS, Brasil
| | - Cristiane Luchese
- a Programa de Pós-graduação em Bioquímica e Bioprospecção (PPGBBio), Grupo de Pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, CEP 96010-900, RS, Brasil
| | - Ethel A Wilhelm
- a Programa de Pós-graduação em Bioquímica e Bioprospecção (PPGBBio), Grupo de Pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, CEP 96010-900, RS, Brasil
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Wang LQ, Zhou HJ, Pan CF, Zhu SM, Xu LM. Expression of IL-1β, IL-6 and TNF-α in rats with thioacetamide-induced acute liver failure and encephalopathy: correlation with brain edema. ASIAN BIOMED 2017. [DOI: 10.5372/1905-7415.0502.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Abstract
Background: Secondary brain edema is a serious complication of hepatic encephalopathy (HE). Recently, it has been reported that proinflammatory cytokines are involved in the pathogenesis of brain edema during HE.
Objectives: Observe the dynamic expressions of brain and plasma proinflammatory cytokines in encephalopathy rats, and evaluate the relationship between proinflammatory cytokines and brain edema.
Methods: Acute HE rats were induced by intraperitoneal injection of thioacetamide (TAA) in 24 hours intervals for two consecutive days. Then, clinical symptom and stages of hepatic encephalopathy, motor activity counts, index of liver function, and brain water content were observed. The dynamic expressions of IL-1β, IL-6, and TNF-α in plasma and brain tissues were measured with enzyme-linked immunosorbent assay.
Results: Typical clinical performances of hepatic encephalopathy were occurred in all TAA-administrated rats. The TAA rats showed lower motor activity counts and higher the index of alanine aminotransferase, aspartate aminotransferase, total bilirubin and ammonia than those in control rats. Brain water content was significantly enhanced in TAA rats compared with the control. The expressions of IL-1β, IL-6, and TNF- α in plasma and brain significantly increased in TAA rats. In addition, the expressions of cerebral proinflammatory cytokines were positively correlated with brain water content but negatively correlated with motor activity counts.Conclusion: Inflammation was involved in the pathogenesis of brain edema during TAA-induced HE.
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Affiliation(s)
- Li-Qing Wang
- Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Heng-Jun Zhou
- Department of Neurosurgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Cai-Fei Pan
- Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Sheng-Mei Zhu
- Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lin-Mei Xu
- Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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Ghiassy B, Rahimi N, Javadi-Paydar M, Gharedaghi MH, Norouzi-Javidan A, Dehpour AR. Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats. Can J Physiol Pharmacol 2016; 95:16-22. [PMID: 28044452 DOI: 10.1139/cjpp-2016-0188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.
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Affiliation(s)
- Bentolhoda Ghiassy
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,b Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Nastaran Rahimi
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Mehrak Javadi-Paydar
- c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Mohammad Hadi Gharedaghi
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Abbas Norouzi-Javidan
- b Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Ahmad R Dehpour
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
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Esteban-Zubero E, Alatorre-Jiménez MA, López-Pingarrón L, Reyes-Gonzales MC, Almeida-Souza P, Cantín-Golet A, Ruiz-Ruiz FJ, Tan DX, García JJ, Reiter RJ. Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review. Pharmacol Res 2016; 105:108-120. [PMID: 26808084 DOI: 10.1016/j.phrs.2016.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/13/2016] [Accepted: 01/15/2016] [Indexed: 02/07/2023]
Abstract
The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonin's ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain.
| | - Moisés Alejandro Alatorre-Jiménez
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Laura López-Pingarrón
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Marcos César Reyes-Gonzales
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Priscilla Almeida-Souza
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Amparo Cantín-Golet
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Francisco José Ruiz-Ruiz
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - José Joaquín García
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
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Saracyn M, Brytan M, Zdanowski R, Ząbkowski T, Dyrla P, Patera J, Wojtuń S, Kozłowski W, Wańkowicz Z. Hepatoprotective effect of nitric oxide in experimental model of acute hepatic failure. World J Gastroenterol 2014; 20:17407-17415. [PMID: 25516652 PMCID: PMC4265599 DOI: 10.3748/wjg.v20.i46.17407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 07/08/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of nitric oxide (NO) on the development and degree of liver failure in an animal model of acute hepatic failure (AHF).
METHODS: An experimental rat model of galactosamine-induced AHF was used. An inhibitor of NO synthase, nitroarginine methyl ester, or an NO donor, arginine, were administered at various doses prior to or after the induction of AHF.
RESULTS: All tested groups developed AHF. Following inhibition of the endogenous NO pathway, most liver parameters improved, regardless of the inhibitor dose before the induction of liver damage, and depending on the inhibitor dose after liver damage. Prophylactic administration of the inhibitor was more effective in improving liver function parameters than administration of the inhibitor after liver damage. An attempt to activate the endogenous NO pathway prior to the induction of liver damage did not change the observed liver function parameters. Stimulation of the endogenous NO pathway after liver damage, regardless of the NO donor dose used, improved most liver function parameters.
CONCLUSION: The endogenous NO pathway plays an important role in the development of experimental galactosamine-induced AHF.
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Bémeur C, Butterworth RF. Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema. Metab Brain Dis 2013; 28:145-50. [PMID: 23212479 DOI: 10.1007/s11011-012-9361-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 11/05/2012] [Indexed: 12/12/2022]
Abstract
A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.
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Affiliation(s)
- Chantal Bémeur
- Département de nutrition, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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9
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Butterworth RF. Reprint of: Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets. Neurochem Int 2012; 60:715-22. [PMID: 22504574 DOI: 10.1016/j.neuint.2012.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 07/20/2011] [Accepted: 07/28/2011] [Indexed: 01/31/2023]
Abstract
It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.
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Affiliation(s)
- Roger F Butterworth
- Neuroscience Research Unit, Saint-Luc Hospital, CHUM, University of Montreal, Montreal, Quebec, Canada.
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Huang HC, Chang CC, Wang SS, Chan CY, Lee FY, Chuang CL, Hsin IF, Teng TH, Lin HC, Lee SD. Pravastatin for thioacetamide-induced hepatic failure and encephalopathy. Eur J Clin Invest 2012; 42:139-45. [PMID: 21749370 DOI: 10.1111/j.1365-2362.2011.02566.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Nitric oxide (NO) inhibition aggravates hepatic damage and encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure. Statins enhance NO production but whether they influence the above parameters are unknown. MATERIAL AND METHODS Male Sprague-Dawley rats were used. In the first series, TAA (350 mg/kg per day, i.p. for 3 days) was administered to induce acute liver failure. Control rats received saline. Rats received distilled water or pravastatin (20 mg/kg per day, p.o.) from 2 days before to 3 days after TAA or saline injection. In the second series, liver cirrhosis was induced by common bile duct ligation (BDL). Sham-operated rats served as controls. Rats received distilled water or pravastatin for 5 or 14 days until the 42nd day after operation. On the last day of treatment, survival, motor activities, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, ammonia and brain histology were evaluated. RESULTS Thioacetamide and BDL rats showed higher ALT, AST, bilirubin and ammonia levels and lower motor activity counts compared with their corresponding control groups. In TAA rats, pravastatin elicited higher total and ambulatory motor activity counts and lower AST and total bilirubin levels. Survival was improved, whereas brain H&E staining was not significantly different in TAA rats with or without pravastatin treatment. In BDL groups, rats with or without pravastatin treatment were not different in motor activity counts and liver biochemistry. CONCLUSIONS Pravastatin ameliorates hepatic encephalopathy and liver biochemistry and improves survival in rats with acute liver failure, but not in those with cirrhosis.
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Affiliation(s)
- Hui-Chun Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan
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Chang CC, Wang SS, Huang HC, Chan CY, Lee FY, Lin HC, Nong JY, Chuang CL, Lee SD. Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat. Eur J Pharmacol 2011; 666:226-32. [DOI: 10.1016/j.ejphar.2011.04.060] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 04/15/2011] [Accepted: 04/18/2011] [Indexed: 01/01/2023]
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12
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Butterworth RF. Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets. Neurochem Int 2011; 59:830-6. [PMID: 21864609 DOI: 10.1016/j.neuint.2011.07.014] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 07/20/2011] [Accepted: 07/28/2011] [Indexed: 12/21/2022]
Abstract
It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.
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Affiliation(s)
- Roger F Butterworth
- Neuroscience Research Unit, Saint-Luc Hospital (CHUM), University of Montreal, Montreal, Quebec, Canada.
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13
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Hsu CY, Lee FY, Huo TI, Chan CY, Huang HC, Lin HC, Chang CC, Teng TH, Wang SS, Lee SD. Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure. J Gastroenterol Hepatol 2010; 25:1321-8. [PMID: 20594263 DOI: 10.1111/j.1440-1746.2010.06235.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. METHODS Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague-Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto-Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)-alpha were determined. RESULTS In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL-1beta, IL-6, IL-10 and TNF-alpha or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF-alpha levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM-treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline-treated rats. CONCLUSIONS Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA-induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.
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Affiliation(s)
- Chia-Yang Hsu
- Divisions of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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14
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Huang HC, Wang SS, Lee FY, Chan CY, Chang FY, Lin HC, Chu CJ, Chen YC, Lee SD. Simvastatin for rats with thioacetamide-induced liver failure and encephalopathy. J Gastroenterol Hepatol 2008; 23:e236-42. [PMID: 17573832 DOI: 10.1111/j.1440-1746.2007.04988.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Nitric oxide (NO) inhibition aggravates hepatic damage and encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure. Statins enhance NO synthase expression beyond their lipid-lowering capability, but the impact on encephalopathy remains unexplored. The aim of this study was to assess the effects of simvastatin on rats with TAA-induced acute liver damage and hepatic encephalopathy. METHODS Sprague-Dawley rats received TAA (350 mg/kg/day) or normal saline (NS) by intraperitoneal injection for 3 consecutive days. Two days before injections, each group was divided into three subgroups, taking (i) distilled water; (ii) simvastatin (20 mg/kg/day); or (iii) simvastatin plus N(G)-nitro-l-arginine methyl ester (L-NAME, 25 mg/kg/day) by oral gavage for 5 days. On the fifth day, severity of encephalopathy was assessed and plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and ammonia were measured. RESULTS The TAA subgroups showed higher ALT, AST, bilirubin and ammonia levels and lower motor activity counts as compared with the NS subgroups. Among the TAA-treated subgroups, rats with simvastatin treatment exerted higher motor activity counts and survival rate (P = 0.043), and a trend of lower ALT, AST, bilirubin and ammonia levels than those receiving saline. All rats that underwent simvastatin plus L-NAME treatment died during or after TAA injections. CONCLUSIONS Simvastatin improved encephalopathy and survival in TAA-administered rats. The beneficial effect was offset by L-NAME, suggesting the role of NO in liver damage and encephalopathy.
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Affiliation(s)
- Hui-Chun Huang
- Division of Gastroenterology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan
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15
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Abstract
Hepatic encephalopathy (HE) is a major complication for acute and chronic liver failure. Despite several decades of intensive clinical and basic research, the pathogenesis of HE is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. These theories are not mutually exclusive and the validity of none of them has been definitely proved experimentally. In this review article, an attractive theory concerning the pathogenesis of HE, the tumour necrosis factor-alpha (TNF) theory, is presented and comprehensively discussed after accumulation of sufficient data which indicate that the pro-inflammatory cytokine, TNF, is strongly involved in the pathogenesis of HE associated with both acute and chronic liver failure. This theory seems to be superior to all other previous theories in the pathogenesis of HE, and may induce development of other beneficial therapeutical modalities for HE directed towards inhibition of TNF production and/or action, and towards enhancement of its degradation.
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Affiliation(s)
- M Odeh
- Bnai Zion Medical Centre, and Faculty of Medicine, Technion, Haifa 31063, Israel.
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16
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Huang HC, Wang SS, Chan CY, Chen YC, Lee FY, Chang FY, Chu CJ, Lin HC, Lu RH, Lee SD. Role of hepatic nitric oxide synthases in rats with thioacetamide-induced acute liver failure and encephalopathy. J Chin Med Assoc 2007; 70:16-23. [PMID: 17276928 DOI: 10.1016/s1726-4901(09)70295-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Hepatic encephalopathy is neuropsychiatric derangement secondary to hepatic decompensation or portal-systemic shunting. Nitric oxide (NO) synthase inhibition aggravates encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure, suggesting a protective role of NO. This study investigated the roles of endothelium-derived constitutive NO synthase (eNOS) and inducible NOS (iNOS) in the liver of rats with fulminant hepatic failure and encephalopathy. METHODS Male Sprague-Dawley rats (300-350 g) were randomized to receive TAA 350 mg/kg/day, by intraperitoneal injection or normal saline for 3 days. Severity of encephalopathy was assessed with the Opto-Varimex animal activity meter. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin were measured. Hepatic iNOS and eNOS RNA and protein expressions were assessed by reverse transcription-polymerase chain reaction and Western blot analyses, respectively. RESULTS The TAA group showed lower motor activity counts than the normal saline group. Hepatic eNOS, but not iNOS, mRNA and protein expressions were enhanced in the TAA group. In addition, hepatic eNOS mRNA expression was negatively correlated with total movement but positively correlated with ALT and AST. Protein expression of hepatic eNOS was positively correlated with ALT, AST and bilirubin. CONCLUSION Upregulation of hepatic eNOS was observed in rats with TAA-induced fulminant hepatic failure and encephalopathy, which might play a regulatory role.
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Affiliation(s)
- Hui-Chun Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C
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17
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Chan CY, Lee FY, Wang TF, Huang SW, Chang FY, Lu RH, Chen YC, Wang SS, Huang HC, Lee SD. Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct-ligated rats with hepatic encephalopathy. J Gastroenterol Hepatol 2006; 21:1483-7. [PMID: 16911697 DOI: 10.1111/j.1440-1746.2006.04261.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Cerebral blood flow regulated by cyclooxygenase (COX) may be involved in the development of HE. There are no comprehensive data concerning the effects of COX inhibition on HE in chronic liver disease. METHODS Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were selected for experiments. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Those rats were then divided into two groups to receive i.p. injection of indomethacin (5 mg/kg per day) or distilled water for 7 days from day 36 to day 42 after BDL. The control group consisted of rats receiving a sham operation. Severity of encephalopathy was assessed by counts of motor activity. Plasma levels of tumor necrosis factor (TNF)-alpha and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), and liver biochemistry tests were determined after treatment. RESULTS The motor activity in both groups of BDL rats were significantly lower than that of the control group (P < 0.001). As compared with the BDL rats treated with distilled water, BDL rats treated with indomethacin had significant lower levels of 6-keto-PGF(1alpha), but the motor activity, TNF-alpha levels and serum biochemistry tests were not significantly different between both BDL groups. CONCLUSIONS Chronic indomethacin administration did not have significantly detrimental or therapeutic effects on the severity of encephalopathy in BDL rats.
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Affiliation(s)
- Cho-Yu Chan
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
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18
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Chu CJ, Chang CC, Wang TF, Lee FY, Chang FY, Chen YC, Chan CC, Huang HC, Wang SS, Lee SD. Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: role of nitric oxide synthase isoforms. J Gastroenterol Hepatol 2006; 21:1194-9. [PMID: 16824075 DOI: 10.1111/j.1440-1746.2006.04310.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. METHOD Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. RESULTS Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01). CONCLUSION Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.
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Affiliation(s)
- Chi-Jen Chu
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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19
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Pawa S, Ali S. Boron ameliorates fulminant hepatic failure by counteracting the changes associated with the oxidative stress. Chem Biol Interact 2006; 160:89-98. [PMID: 16442087 DOI: 10.1016/j.cbi.2005.12.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 11/30/2005] [Accepted: 12/05/2005] [Indexed: 11/29/2022]
Abstract
Boron has well-defined biological effects and may be of therapeutic benefit. In the current paper, the effect of boron in the form of borax was tested in experimental animal model of fulminant hepatic failure (FHF). The syndrome was induced in female Wistar rats by three consecutive daily intraperitoneal injections of thioacetamide (400 mg/kg). In the treatment groups, rats received borax (4.0 mg/kg) orally for three consecutive days followed by thioacetamide. The group administered with thioacetamide plus vehicle, and the borax alone treated rats served as controls. In all groups, rats were terminated 4 h after administering the last dose of thioacetamide, and the tissue/serum was used to measure hepatic levels of thiobarbituric acid reactive substances, reduced glutathione, and various enzymes associated with oxidative stress including peroxide metabolizing enzymes and xanthine oxidase. In thioacetamide treated group, many fold increase in the activity level of serum marker enzymes suggesting FHF was observed that could be brought down significantly in rats receiving boron. Modulation and a correlation in the activity level of oxidant generating enzyme and lipid peroxidation as well as hepatic glutathione level was also observed in rats receiving thioacetamide. In the group receiving boron followed by thioacetamide, these changes could be minimized moderately. The activity level of the peroxide metabolizing enzymes and the tripeptide glutathione, which decreased following thioacetamide treatment were moderately elevated in the group receiving boron followed by thioacetamide. The data clearly shows that borax partly normalizes the liver and offsets the deleterious effects observed in FHF by modulating the oxidative stress parameters.
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Affiliation(s)
- Sonica Pawa
- Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard University, Hamdard Nagar, New Delhi 1100 62, India
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20
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Barshes NR, Gay AN, Williams B, Patel AJ, Awad SS. Support for the Acutely Failing Liver: A Comprehensive Review of Historic and Contemporary Strategies. J Am Coll Surg 2005; 201:458-76. [PMID: 16125082 DOI: 10.1016/j.jamcollsurg.2005.04.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2005] [Revised: 03/23/2005] [Accepted: 04/11/2005] [Indexed: 12/16/2022]
Affiliation(s)
- Neal R Barshes
- Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
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21
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Chu CJ, Hsiao CC, Wang TF, Chan CY, Lee FY, Chang FY, Chen YC, Huang HC, Wang SS, Lee SD. Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure. World J Gastroenterol 2005; 11:232-6. [PMID: 15633222 PMCID: PMC4205408 DOI: 10.3748/wjg.v11.i2.232] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure.
METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay.
RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-α (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S.
CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.
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Affiliation(s)
- Chi-Jen Chu
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China
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22
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Hernández R, Martínez-Lara E, Del Moral ML, Blanco S, Cañuelo A, Siles E, Esteban FJ, Pedrosa JA, Peinado MA. Upregulation of endothelial nitric oxide synthase maintains nitric oxide production in the cerebellum of thioacetamide cirrhotic rats. Neuroscience 2004; 126:879-87. [PMID: 15207323 DOI: 10.1016/j.neuroscience.2004.04.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2004] [Indexed: 02/01/2023]
Abstract
This study examines the expression and cellular distribution pattern of nitric oxide synthase (NOS) isoforms, nitrotyrosine-derived complexes, and the nitric oxide (NO) production in the cerebellum of rats with cirrhosis induced by thioacetamide (TAA). The results showed local changes in the tissue distribution pattern of the NOS isoforms and nitrated proteins in the cerebellum of these animals. Particularly, eNOS immunoreactivity in perivascular glial cells of the white matter was detected only in TAA-treated animals. In addition, although neither neuronal NOS (nNOS) nor inducible NOS (iNOS) cerebellar protein levels appeared to be affected, the endothelial NOS (eNOS) isoform significantly increased its expression, and NO production slightly augmented in TAA-treated rats. These NOS/NO changes may contribute differently to the evolution of the hepatic disease either by maintaining the guanosine monophosphate-NO signal transduction pathways and the physiological cerebellar functions or by inducing oxidative stress and cell damage. This model gives rise to the hypothesis that the upregulation of the eNOS maintains the physiological production of NO, while the iNOS is silenced and the nNOS remains unchanged. The differential NOS-distribution and expression pattern may be one of the mechanisms involved to balance cerebellar NO production in order to minimize TAA toxic injury. These data help elucidate the role of the NOS/NO system in the development and progress of hepatic encephalopathy associated with TAA cirrhosis.
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Affiliation(s)
- R Hernández
- Department of Experimental Biology (Edf B3), University of Jaén, Paraje Las Lagunillas s/n, 23071 Jaén, Spain
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Farghali H, Canová N, Kucera T, Martínek J, Masek K. Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects. Int Immunopharmacol 2004; 3:1627-38. [PMID: 14555288 DOI: 10.1016/s1567-5769(03)00185-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Effects of endotoxemia-induced NO production on rat liver and hepatocytes in culture were investigated. Rats were treated intraperitoneally with saline, lipopolysaccharide (LPS, 10 mg/kg), L-nitroarginine methyl ester (L-NAME)+LPS, aminoguanidine (AG)+LPS, FK 506+LPS, S-nitroso-N-acetyl penicillamine (SNAP)+L-NAME+LPS and SNAP+FK 506+LPS. Mortality, hepatocyte viability and liver function test were estimated. Liver morphology was observed by light and electron microscopy. Hepatocyte cultures were treated with LPS, cytokine mixture (CM) with or without FK 506, L-NAME or AG. Hepatocyte function and inducible form of NOS (iNOS) expression were evaluated. Twenty-four hours after treatments with saline, LPS, L-NAME+LPS, AG+LPS, FK 506+LPS, SNAP+L-NAME+LPS and SNAP+FK 506+LPS, rat mortalities were 0%, 10%, 48%, 8%, 20%, 38% and 0%, and hepatocyte viabilities were 93+/-3%, 80+/-3%, 52+/-8%, 88+/-1%, 70+/-3%, 80+/-4% and 82+/-3%, respectively. AG+LPS or L-NAME+LPS administration was followed by excessive vacuolization of hepatocytes with lesions in the intermediary lobule zone characterized by features of secondary necrosis as a continuation of apoptotic processes. SNAP+L-NAME+LPS resulted in a well-preserved structure of central vein lobules with sparse signs of apoptosis. Treatment with LPS or CM increased iNOS expression in hepatocyte culture, which was inhibited by L-NAME, FK 506 or AG. AG reduced LPS-induced rise in alanine aminotransferase leakage. LPS-induced NO exerts cytoprotective effects in vivo, while LPS-induced NO in vitro appears to be toxic. Based on the data of this report, one cannot use in vitro results to predict in vivo responses to LPS-induced NO production. The pharmacological modulation of iNOS expression or NO production in vivo or in vitro, therefore, by the development of specific NO donors or inhibitors is promising for improvement of hepatocyte functions under the two experimental conditions, respectively.
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Affiliation(s)
- Hassan Farghali
- Institute of Pharmacology, 1st Faculty of Medicine, Charles University, Albertov 4, 128 00, 2, Prague, Czech Republic.
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Odeh M, Sabo E, Srugo I, Oliven A. Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int 2004; 24:110-6. [PMID: 15078474 DOI: 10.1111/j.1478-3231.2004.0894.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several studies have shown that serum levels of tumor necrosis factor-alpha (TNF) are significantly elevated in patients with acute and chronic liver diseases, where these elevations are independent of the etiology of the underlying disease. Serum levels of TNF are significantly higher in patients with cirrhosis than in those without cirrhosis, reaching the highest levels in decompensated cirrhosis. It has also been shown that plasma levels of TNF correlate with the severity of hepatic encephalopathy (HE) in fulminant hepatic failure. However, still there are no published data regarding the relationship between blood levels of TNF and the presence or severity of HE in patients with chronic liver failure. AIM The aim of this study is to determine the relationship between serum levels of TNF and clinical grades of HE in patients with liver cirrhosis. METHODS Using a commercially available high-sensitivity enzyme-linked immunosorbent assay kit, serum levels of TNF were measured in 74 patients with liver cirrhosis in various clinical grades of HE (grades 0-4). RESULTS The mean+/-SEM values of serum levels of TNF at presentation in patients with grade 0 of HE (n=23), grade 1 (n=12), grade 2 (n=14), grade 3 (n=16), and grade 4 (n=9) were 4.50+/-0.46, 9.10+/-1.0, 12.98+/-1.22, 21.51+/-2.63, and 58.26+/-19.7 pg/ml, respectively. A significant positive correlation was found between serum levels of TNF and the severity of HE (P<0.0001). CONCLUSION Serum levels of TNF correlate positively with the severity of HE in patients with chronic liver failure.
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Affiliation(s)
- M Odeh
- Department of Internal Medicine B, Bnai Zion Medical Center, Technion Faculty of Medicine, Israel Institute of Technology, Haifa, Israel.
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25
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Chan CY, Huang SW, Wang TF, Lu RH, Lee FY, Chang FY, Chu CJ, Chen YC, Chan CC, Huang HC, Lee SD. Lack of detrimental effects of nitric oxide inhibition in bile duct-ligated rats with hepatic encephalopathy. Eur J Clin Invest 2004; 34:122-8. [PMID: 14764075 DOI: 10.1111/j.1365-2362.2004.01295.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Vasodilatation induced by nitric oxide (NO) may be involved in the development of HE. There is no comprehensive data concerning the effects of NO inhibition on HE in chronic liver disease. METHODS Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were selected for experiments. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Counts of movements were compared between BDL rats and rats receiving a sham operation. In another series of experiments, BDL rats received either Nomega-nitro-L-arginine methyl ester (L-NAME, 25 mg kg-1 day-1 in tap water) or tap water (control) from the 36th to 42nd days after BDL. Besides motor activities, plasma levels of tumour necrosis factor (TNF)-alpha and nitrate/nitrite, liver biochemistry tests and haemodynamics were determined after treatment. RESULTS Compared with the sham-operated rats, the total, ambulatory and vertical movements were significantly decreased in the BDL rats (P </= 0.001). The L-NAME group had a significantly higher mean arterial pressure than that of the control group (119.0 +/- 2.5 mmHg vs. 97.3 +/- 2.8 mmHg, P = 0.002). However, the counts of motor activities, plasma levels of TNF-alpha and nitrate/nitrite, and serum biochemistry tests were not significantly different between the L-NAME and control groups. CONCLUSIONS Bile duct ligation may induce HE evidenced by a decrease in motor activities. However, chronic L-NAME administration did not have significantly detrimental or therapeutic effects on the severity of encephalopathy in BDL rats.
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Affiliation(s)
- C-Y Chan
- Taipei Veterans General Hospital, Armed Forces Sungshan Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan
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Gonzaga Silva LF, Odorico de Moraes M, Santos Dias Soares F, Mota Moura Fé D, Cavalcante JLBG, Anselmo JNN, Leitao Vasconcelos PR. Effects of l-arginine-enriched total enteral nutrition on body weight gain, tumor growth, and in vivo concentrations of blood and tissue metabolites in rats inoculated with Walker tumor in the kidney. Nutrition 2004; 20:225-9. [PMID: 14962691 DOI: 10.1016/j.nut.2003.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE We evaluated the effects of l-arginine-enriched total enteral nutrition (LATEN) on tumor-free and right kidney tumor-bearing rats through the determination of in vivo concentrations of metabolites to better understand intermediary metabolism in this model. METHODS Rats were individually housed in wire cages within a controlled environment (25 degrees C and 50% relative humidity) and exposed to a 12-h light-and-dark cycle. Rats comprised the following groups: tumor-free on enteral nutrition plus l-amino acid (n = 8); tumor-free on enteral nutrition plus l-arginine (n = 8); tumor bearing on enteral nutrition plus l-amino acids (n = 8); and tumor bearing on enteral nutrition plus l-arginine (n = 8). Rats had their right kidneys inoculated with saline or tumor cells and were subjected to laparotomy or gastrostomy on day 1 and received chow diet for the next 2 days. Gastrostomy with enteral nutrition was performed on days 3 to 9. On day 9, body weight gain, tumor growth as volume, in vivo blood (microM/mL), and tissue (microM/g) metabolite concentrations were determined. The Mann-Whitney U test was used to test significance. RESULTS LATEN in tumor-free rats decreased liver (0.25 +/- 0.03 versus 0.13 +/- 0.03 micromol/g, P < 0.05) and right kidney (0.13 +/- 0.1 versus 0.04 +/- 0.00 micromol/g, P < 0.05) ketone body concentrations. LATEN in tumor-bearing rats decreased blood pyruvate (0.17 +/- 0.01 versus 0.10 +/- 0.008 microM/mL, P < 0.005), lactate (5.2 +/- 0.3 versus 2.9 +/- 0.28 microM/mL, P < 0.01), and glucose (6.4 +/- 0.8 versus 3.7 +/- 0.5 microM/mL, P < 0.05). Glucose concentrations decreased in liver (13.9 +/- 2.0 versus 4.89 +/- 0.6 microM/g, P < 0.005) and tumor (3.5 +/- 0.8 versus 1.41 +/- 0.3 microM/g, P < 0.05). There were no changes in body weight gain (21 +/- 2.0 versus 30.3 +/- 3.6 g) or tumor growth (1.53 +/- 0.1 versus 1.26 +/- 0.01 cm(3)). CONCLUSIONS LATEN decreased ketone body concentrations in liver and kidney in tumor-free rats, possibly due to lower ketogenesis and decreased kidney uptake. In tumor-bearing rats, LATEN decreased lacticemia and glycemia and pyruvate blood concentrations. LATEN also reduced liver and tumor glucose concentrations in tumor-bearing animals. The possibility of LATEN-induced insulin and insulin-like growth factor-1 liberation signaling these changes is discussed.
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Affiliation(s)
- Lúcio Flávio Gonzaga Silva
- Department of Surgery, Federal University of Ceará, CEP 60.430-140, Rodolfo Teófilo, Fortaleza, Ceará, Brazil.
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Bruck R, Aeed H, Avni Y, Shirin H, Matas Z, Shahmurov M, Avinoach I, Zozulya G, Weizman N, Hochman A. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J Hepatol 2004; 40:86-93. [PMID: 14672618 DOI: 10.1016/s0168-8278(03)00504-x] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.
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Affiliation(s)
- Rafael Bruck
- Department of Gastroenterology, The E. Wolfson Medical Center, Holon 58100, Israel.
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