Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

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Uchiyama, Munehito; Tojo, Kentaro; Yazawa, Takuya; Ota, Shuhei; Goto, Takahisa; Kurahashi, Kiyoyasu

2015-04-01

Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R. Copyright © 2015 Elsevier Inc. All rights reserved.

CT of hepatic and splenic injury in children: Role in the decision for laparotomy

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Brick, S.H.; Taylor, G.A.; Potter, B.M.; Eichelberger, M.R.

1987-01-01

Two hundred seventy-four children were examined with CT after incurring blunt trauma to the abdomen. Hepatic and/or splenic injuries were detected in 36 patients. Of 12 children with moderate to severe hepatic injuries, only one required operative intervention. Of 13 children with moderate to sever splenic injuries, only one required splenorrhaphy. Only two of 16 patients with a moderate to large hemoperitoneum required surgery for hepatic or splenic injury. The authors conclude that the decision for laparotomy should not be based on the extent of injury as seen on CT, but on the physiologic condition of the child

Treatment of penetrating hepatic injuries: a retrospective analysis of 50 patients.

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Gonullu, D; Koksoy, F N; Ilgun, S; Demiray, O; Yucel, O; Yucel, T

2009-01-01

The aim of this study was to determine the possibility of non-operative treatment via retrospective analysis of our patients. Fifty patients with penetrating hepatic injuries were examined retrospectively with respect to trauma scores, associated injuries, complications, and mortality parameters. Thirteen injuries were caused by firearms, whereas 37 injuries were caused by stab wounds. Forty-three patients (86%) underwent laparotomy and 7 patients (14%) were monitored by CT and clinical findings (nonoperative group, NO group). The laparotomies were evaluated as non-therapeutic in 11 patients (22%) (NTL group) and therapeutic in 32 patients (64%) (TL group). The morbidity and mortality rates were 40 and 10%, respectively. RTS and ISS scores of the nonsurviving and the surviving patients were significantly different. The rates of major venous, grade IV-V hepatic injuries, and gunshot wounds were significantly higher in the nonsurviving patients when compared to the surviving patients. Major venous and grade IV-V hepatic injuries were the primary factors determining mortality and these injuries generally occurred as a result of firearm injuries. NTL occurring at a rate of 22% would decrease to 2% if 'RTS <7' criteria was added to the hemodynamic instability and/or peritoneal irritation findings determining surgical candidacy. Copyright 2009 S. Karger AG, Basel.

Limitations of nonoperative management of type IIIb blunt hepatic injuries in hemodynamically stable patients after fluid resuscitation

International Nuclear Information System (INIS)

Sekine, Kazuhiko; Kitano, Mitsuhide; Shimizu, Masayuki; Matsumoto, Shokei; Yoshii, Hiroshi; Yamazaki, Motoyasu; Aikawa, Naoki

2007-01-01

Nonoperative management (NOM) of hepatic injuries caused by blunt trauma in hemodynamically stable patients is widely accepted, but the feasibility of NOM for severe hepatic injuries has not been fully evaluated. Among all patients with blunt severe hepatic injury (type IIIb) admitted to Saiseikai Kanagawa-ken Hospital and Keio University Hospital from 1988 to 2004, those who had been hemodynamically stable after fluid resuscitation at the emergency department were initially managed nonoperatively. We reviewed demographic, physiological, and laboratory data; computed tomography (CT) findings; 80-day cumulative laparotomy rate; and complications. The anatomical severity of the hepatic injuries was evaluated based on the CT findings, such as hepatic vein injuries and area lacerated according to the Couinaud liver segment. In patients who underwent surgery after admission, the surgical indications and operative findings were reviewed. Overall, 34 consecutive patients were enrolled in this study. Five patients underwent surgery, and all of their surgical indications were attributable to liver-related complications after injury. The indication for surgery was hemodynamic instability in 3 patients with hepatic vein injures in the early phase (<15 hours after estrogen receptor (ER) arrival) and intra-abdominal septic complications in 2 patients in the late phase (hospital days 14 and 64). The cumulative 80-day laparotomy rate in the early phase was significantly higher (p<0.0001) in the patients suspected of having hepatic vein injury, and in the late phase it was higher (p=0.002) in those with injuries in 4 or more segments of hepatic injuries. For the successful NOM of blunt hepatic injury type IIIb in patients who are hemodynamically stable after fluid resuscitation, a strong suspicion of concurrent hepatic vein injury is critical in the early phase, and laceration in 4 or more segments should be noted in the late phase. (author)

Osthole attenuates hepatic injury in a rodent model of trauma-hemorrhage.

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Yu, Huang-Ping; Liu, Fu-Chao; Tsai, Yung-Fong; Hwang, Tsong-Long

2013-01-01

Recent evidences show that osthole possesses anti-inflammatory properties and protective effects following shock-like states, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase (p38 MAPK) pathway exerts anti-inflammatory effects in injury. The aim of this study was to investigate whether p38 MAPK plays any role in the osthole-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of osthole (3 mg/kg, intravenously) with and without a p38 MAPK inhibitor SB-203580 (2 mg/kg, intravenously), SB-203580 or vehicle was administered. Plasma alanine aminotransferase (ALT) with aspartate aminotransferase (AST) concentrations and various hepatic parameters were measured (n = 8 rats/group) at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the osthole-treated rats subjected to trauma-hemorrhage. Osthole treatment also increased hepatic phospho-p38 MAPK expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 with osthole abolished the osthole-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of osthole administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through p38 MAPK-dependent pathway.

Efficacy of 131I treatment for 840 cases of Graves' disease combined with hepatic function injury

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Yin Liang; Tan Jian; Wang Renfei

2012-01-01

Objective: To assess the efficacy of 131 I treatment for Graves' disease (GD) complicated with hepatic function injury in order to provide guidance for clinical practice. Methods: A total of 840 GD cases complicated with hepatic function injury were retrospectively reviewed after 131 I treatment. Analysis of variance and Dunnett t test were used to compare serum FT 3 , FT 4 , and TSH levels before and 1, 3, and 6 months after 131 I therapy. R × C table χ 2 test was used to compare therapeutic efficacies among cases with different degrees and types of hepatic function injuries. Analysis of variance and Dunnett t test were used to evaluate recovery time of different degrees of hepatic function injuries. Cross classification 2 × 2 table correlation analysis was adopted to assess the correlation between 131 I therapeutic efficacies of GD and recovery efficacies of hepatic function. Results: The curative rate for GD was 76.8% (645/840). There were significant changes of FT 3 ((25.74 ± 5.81), (15.54 ± 4.12), (12.76 ± 2.35) and (7.95 ± 1.64) pmol/L, respectively; F=5007.958, t=54.455, 69.297 and 94.976, all P<0.05), FT 4 ((75.84 ± 16.78), (45.69 ±8.96), (36.81 ± 5.03) and (25.17 ±.4.46) pmol/L, respectively; F=3876.410, t=513.602, 664.871 and 863.157, all P<0.05) and TSH ((0.01 ±0.02), (0.02±0.08), (0.85 ±0.36) and (1.26 ± 0.54) mU/L, respectively; F=3050.430, t=2.627, 46.989 and 78.315, all P<0.05) before and 1,3,and 6 months after 131 I treatment. The curative rate of hepatic function abnormality was 79.2% (665/840). For mild, medium and severe hepatic function injury patients, curative rates were 88.4% (420/475), 68.8% (214/311) and 57.4% (31/54), respectively. The curative rate of patients with mild hepatic function injury was significantly higher than those with medium and severe hepatic function injury (χ 2 =46.338, 37.100, respectively, both P<0.01), and the recovery time was significantly shorter in patients with mild hepatic function injury

Blunt hepatic and splenic trauma in children: correlation of a CT injury severity scale with clinical outcome

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Ruess, L. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Sivit, C.J. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States)]|[Dept. of Pediatrics, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Eichelberger, M.R. [Dept. of Pediatrics, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States)]|[Dept. of Surgery, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences Washington, DC (United States); Taylor, G.A. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Bond, S.J. [Dept. of Surgery, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences Washington, DC (United States)

1995-07-01

The purpose of this report is to compare a computed tomography (CT) injury severity scale for hepatic and splenic injury with the following outcome measures: requirement for surgical hemostasis, requirement for blood transfusion and late complications. Sixty-nine children with isolated hepatic injury and 53 with isolated splenic injury were prospectively classified at CT according to extent of parenchymal involvement. Clinical records were reviewed to determine clinical outcome. Ninety-seven children (80%) were managed non-operatively without transfusion. One child with hepatic injury required surgical hemostasis, and 17 (25%) required transfusion of blood. Increasing severity of hepatic injury at CT was associated with progressively greater frequency of transfusion (P = 0.002 by {chi}{sup 2}-test). One child with splenic injury underwent surgery and eight (15%) required transfusion of blood. Splenic injury grade at CT did not correlate with frequency (P = 0.41 by {chi}{sup 2}-test) or amount (P = 0.35 by factorial analysis of variance) of transfusion. There was one late complication in the nonsurgical group. A majority of children with hepatic and splenic injury were managed non-operatively without requiring blood transfusion. The severity of injury by CT scan did not correlate with need for surgery. Increasing grade of hepatic injury at CT was associated with increasing frequency of blood transfusion. CT staging was not discriminatory in predicting transfusion requirement in splenic injury. (orig.)

Blunt hepatic and splenic trauma in children: correlation of a CT injury severity scale with clinical outcome

International Nuclear Information System (INIS)

Ruess, L.; Sivit, C.J.; Eichelberger, M.R.; Taylor, G.A.; Bond, S.J.

1995-01-01

The purpose of this report is to compare a computed tomography (CT) injury severity scale for hepatic and splenic injury with the following outcome measures: requirement for surgical hemostasis, requirement for blood transfusion and late complications. Sixty-nine children with isolated hepatic injury and 53 with isolated splenic injury were prospectively classified at CT according to extent of parenchymal involvement. Clinical records were reviewed to determine clinical outcome. Ninety-seven children (80%) were managed non-operatively without transfusion. One child with hepatic injury required surgical hemostasis, and 17 (25%) required transfusion of blood. Increasing severity of hepatic injury at CT was associated with progressively greater frequency of transfusion (P = 0.002 by χ 2 -test). One child with splenic injury underwent surgery and eight (15%) required transfusion of blood. Splenic injury grade at CT did not correlate with frequency (P = 0.41 by χ 2 -test) or amount (P = 0.35 by factorial analysis of variance) of transfusion. There was one late complication in the nonsurgical group. A majority of children with hepatic and splenic injury were managed non-operatively without requiring blood transfusion. The severity of injury by CT scan did not correlate with need for surgery. Increasing grade of hepatic injury at CT was associated with increasing frequency of blood transfusion. CT staging was not discriminatory in predicting transfusion requirement in splenic injury. (orig.)

Serum sphingomyelin has potential to reflect hepatic injury in chronic hepatitis B virus infection

OpenAIRE

Su-Jun Zheng; Feng Qu; Jun-Feng Li; Jing Zhao; Jing-Yun Zhang; Mei Liu; Feng Ren; Yu Chen; Jin-Lan Zhang; Zhong-Ping Duan

2015-01-01

Objective: To explore the relation between serum sphingolipids and hepatic injury in chronic HBV infection. Methods: A cohort of participants including 48 healthy persons, 103 chronic HBV-infected patients containing chronic hepatitis B (CHB) and HBV-related cirrhosis were included. High performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was performed to detect serum sphingolipids. The serological indicators were detected and quantified. The valid liver biop...

[Management of hepatic injuries with multiple trauma in the emergency unit. Report of three cases].

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Qamouss, Y; Belyamani, L; Azendour, H; Balkhi, H; Haimeur, C; Atmani, M

2006-01-01

The problems put by the blunt hepatic injuries at the multiple traumas are discussed after the exposition of three observations. 60% of the blunt hepatic injuries are due to the accidents of the public way. The strategy diagnosis and therapeutic facing a hepatic lesion remains guided by the patient's state haemodynamic. The exam essential to the arrival in the sieve of the emergencies is the abdominal scan that searches for one extrusion intra and possibly retroperitoneal and analyze the hepatic parenchyrma. However, it depends extensively on the experience of the echographist. The city scan stood to the first plan of the medical imagery: it permits a precise diagnosis of the parenchymateuses hepatic lesions, specify the abundance of the hemoperitoine, facilitate the therapeutic conduct in presence of associated lesions and the surveillance of the blunt hepatic injuries.

Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model.

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Jiang, Jun; Wei, Jishu; Wu, Junli; Gao, Wentao; Li, Qiang; Jiang, Kuirong; Miao, Yi

2016-01-01

Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury.

Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model

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Jun Jiang

2016-01-01

Full Text Available Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury.

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.

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Gehrke, Nadine; Nagel, Michael; Straub, Beate K; Wörns, Marcus A; Schuchmann, Marcus; Galle, Peter R; Schattenberg, Jörn M

2018-03-01

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP -/- ) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68 + macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP -/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP -/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological

Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice.

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Iracheta-Vellve, Arvin; Petrasek, Jan; Gyogyosi, Benedek; Bala, Shashi; Csak, Timea; Kodys, Karen; Szabo, Gyongyi

2017-07-01

Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown. In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH. We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH. Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Two clinically relevant pressures of carbon dioxide pneumoperitoneum cause hepatic injury in a rabbit model

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Li, Jun; Liu, Ying-Hai; Ye, Zhan-Yong; Liu, He-Nian; Ou, Shan; Tian, Fu-Zhou

2011-01-01

AIM: To observe the hepatic injury induced by carbon dioxide pneumoperitoneum (CDP) in rabbits, compare the effects of low- and high-pressure pneumoperitoneum, and to determine the degree of hepatic injury induced by these two clinically relevant CDP pressures.

Mesh wrapping for severe hepatic injury: a beneficial option in the trauma surgeon's armamentarium.

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Kennedy, Ryan; Brevard, Sidney B; Bosarge, Patrick; Simmons, Jon D; Frotan, Mohammed A; Baker, Jeremy A; Tuart, Lynda; Pritchett, Cindy; Gonzalez, Richard P

2015-03-01

The purpose of this study was to assess the efficacy of absorbable mesh wrapping (MW) versus perihepatic packing (HP) for severe hepatic injury. From January 2001 to December 2012, data were collected for MW patients with hepatic injury. Patients who underwent HP were matched with MW patients by injury mechanism, liver injury grade, Injury Severity Score, and age. Twenty-six MW and twenty-six HP patients were matched. Eighteen blunt and 8 penetrating injuries were present in each group. There were 9 (35%) mortalities in the MW group and 16 (62%) in the HP groups (P = .03). Average transfusions were 12.0 and 24.5 (P = .03) packed red blood cells in the MW and HP groups, respectively. Average laparotomies per survivors were 1.3 for the MW and 3.1 for the HP groups (P = .01). Average length of stay for survivors was 19 and 47 (P = .04) days in the MW and HP groups, respectively. MW for hepatic injuries can significantly decrease mortality, transfusions, laparotomies, and length of stay. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

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Abdel-Gaber, Seham A; Ibrahim, Mohamed A; Amin, Entesar F; Ibrahim, Salwa A; Mohammed, Rehab K; Abdelrahman, Aly M

2015-08-01

Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.

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Lídia Cedó

Full Text Available Human hepatic lipase (hHL is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT. In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL-mediated free fatty acid (FFA lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.

Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.

Science.gov (United States)

Cedó, Lídia; Santos, David; Roglans, Núria; Julve, Josep; Pallarès, Victor; Rivas-Urbina, Andrea; Llorente-Cortes, Vicenta; Laguna, Joan Carles; Blanco-Vaca, Francisco; Escolà-Gil, Joan Carles

2017-01-01

Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.

Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

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Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

2008-10-01

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis.

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Verdonk, Robert C; Lozano, Mallaki F; van den Berg, Aad P; Gouw, Annette S H

2016-09-01

The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. Cases of newly diagnosed, untreated autoimmune hepatitis without overlap syndrome were selected. Pretreatment and follow up biopsies were scored for inflammation, fibrosis, bile ductal injury and ductular reaction. Thirty-five cases were studied of whom 14 cases had follow up biopsies. Bile duct injury was present in 29 cases (83%), mostly in a PBC-like pattern and was not correlated with demographical or laboratory findings. Ductular reaction, observed in 25 of 35 cases (71%) using conventional histology and in 30 of 32 cases (94%) using immunohistochemistry, was correlated with portal and lobular inflammation, interface hepatitis and centrilobular necrosis as well as bile duct injury and fibrosis. In 11 of 14 cases (79%) ductular reaction remained present on post-treatment biopsy whereas bile duct injury persisted in six of 14 (43%) of cases. Bile duct injury and ductular reaction are very common in newly diagnosed autoimmune hepatitis and cannot be predicted biochemically. Bile duct injury may subside in the majority of treated AIH cases while DR tends to persist during follow up. These findings show that the two phenomena are part of the spectrum of AIH with dissimilar responses to treatment and do not necessarily point towards an overlap syndrome. Persistence of ductular reaction after treatment supports the notion that it represents a regenerative response. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Differential Effects of Three Techniques for Hepatic Vascular Exclusion during Resection for Liver Cirrhosis on Hepatic Ischemia-Reperfusion Injury in Rats

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Changjun Jia

2018-01-01

Full Text Available Background/Aims. Hepatic ischemia-reperfusion (I/R injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods. Liver cirrhotic rats had undertaken Pringle maneuver (PR, hemihepatic vascular occlusion (HH, or hepatic blood inflow occlusion without hemihepatic artery control (WH. Levels of tumor necrosis factor alpha (TNF-α, nuclear factor kappa B (NF-κB, toll-like receptor 4 (TLR4, TIR-domain-containing adapter-inducing interferon-β (TRIF, and hemeoxygenase 1 (HMOX1 were assayed. Results. The histopathologic analysis displayed that liver harm was more prominent in the PR group, but similar in the HH and WH groups. The HH and WH groups responded to hepatic I/R inflammation similarly but better than the PR group. Mechanical studies suggested that TNF-α/NF-κB signaling and TLR4/TRIF transduction pathways were associated with the differential effects. In addition, the HH and WH groups had significantly higher levels of hepatic HMOX1 (P<0.05 than the PR group. Conclusions. HH and WH confer better preservation of liver function and protection than the Pringle maneuver in combating I/R injury. Upregulation of HMOX1 may lead to better protection and clinical outcomes after liver resection.

Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.

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Shin, So Youn; Jeong, Sook-Hyang; Sung, Pil Soo; Lee, Jino; Kim, Hyung Joon; Lee, Hyun Woong; Shin, Eui-Cheol

2016-05-01

Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

Promoting effect of adipocytokine, apelin, on hepatic injury in ...

African Journals Online (AJOL)

Marwa N. Emam

2015-12-14

Dec 14, 2015 ... and inflammatory markers, pancreatic and hepatic MPO activity with ..... ment, and possibly mediated by an apelin-induced reduction ... So targeting the ape- .... Adenoviral delivery of human and viral IL-10 in murine sepsis.

Methimazole protects lungs during hepatic ischemia-reperfusion injury in rats: an effect not induced by hypothyroidism.

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Tütüncü, Tanju; Demirci, Cagatay; Gözalan, Ugur; Yüksek, Yunus Nadi; Bilgihan, Ayse; Kama, Nuri Aydin

2007-05-01

Hepatic ischemia-reperfusion injury may lead to remote organ failure with mortal respiratory dysfunction. The aim of the present study was to analyze the possible protective effects of methimazole on lungs after hepatic ischemia-reperfusion injury. Forty male Wistar albino rats were randomized into five groups: a control group, in which bilateral pulmonary lobectomy was done; a hepatic ischemia-reperfusion group, in which bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion; a thyroidectomy-ischemia-reperfusion group (total thyroidectomy followed by, 7 days later, bilateral pulmonary lobectomy after hepatic ischemia-reperfusion); a methimazole-ischemia-reperfusion group (following methimazole administration for 7 days, bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion); and a methimazole +L-thyroxine-ischemia-reperfusion group (following methimazole and L-thyroxine administration for 7 days, bilateral pulmonary lobectomy was performed after hepatic ischemia-reperfusion). Pulmonary tissue specimens were evaluated histopathologically and for myeloperoxidase and malondialdehyde levels. All of the ischemia-reperfusion intervention groups had higher pulmonary injury scoring indices than the control group (P < 0.001). Pulmonary injury index of the ischemia-reperfusion group was higher than that of both the methimazole-supplemented hypothyroid and euthyroid groups (P = 0028; P = 0,038, respectively) and was similar to that of the thyroidectomized group. Pulmonary tissue myeloperoxidase and malondialdehyde levels in the ischemia-reperfusion group were similar with that in the thyroidectomized rats but were significantly higher than that in the control, and both the methimazole-supplemented hypothyroid and euthyroid groups. Methimazole exerts a protective role on lungs during hepatic ischemia-reperfusion injury, which can be attributed to its anti-inflammatory and anti-oxidant effects rather than hypothyroidism alone.

Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

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Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

2014-07-08

An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP

Nonoperative management of blunt hepatic injury: an Eastern Association for the Surgery of Trauma practice management guideline.

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Stassen, Nicole A; Bhullar, Indermeet; Cheng, Julius D; Crandall, Marie; Friese, Randall; Guillamondegui, Oscar; Jawa, Randeep; Maung, Adrian; Rohs, Thomas J; Sangosanya, Ayodele; Schuster, Kevin; Seamon, Mark; Tchorz, Kathryn M; Zarzuar, Ben L; Kerwin, Andrew

2012-11-01

During the last century, the management of blunt force trauma to the liver has changed from observation and expectant management in the early part of the 1900s to mainly operative intervention, to the current practice of selective operative and nonoperative management. These issues were first addressed by the Eastern Association for the Surgery of Trauma in the Practice Management Guidelines for Nonoperative Management of Blunt Injury to the Liver and Spleen published online in 2003. Since that time, a large volume of literature on these topics has been published requiring a reevaluation of the previous Eastern Association for the Surgery of Trauma guideline. The National Library of Medicine and the National Institutes of Health MEDLINE database were searched using PubMed (http://www.pubmed.gov). The search was designed to identify English-language citations published after 1996 (the last year included in the previous guideline) using the keywords liver injury and blunt abdominal trauma. One hundred seventy-six articles were reviewed, of which 94 were used to create the current practice management guideline for the selective nonoperative management of blunt hepatic injury. Most original hepatic guidelines remained valid and were incorporated into the greatly expanded current guidelines as appropriate. Nonoperative management of blunt hepatic injuries currently is the treatment modality of choice in hemodynamically stable patients, irrespective of the grade of injury or patient age. Nonoperative management of blunt hepatic injuries should only be considered in an environment that provides capabilities for monitoring, serial clinical evaluations, and an operating room available for urgent laparotomy. Patients presenting with hemodynamic instability and peritonitis still warrant emergent operative intervention. Intravenous contrast enhanced computed tomographic scan is the diagnostic modality of choice for evaluating blunt hepatic injuries. Repeated imaging should be

NKT cells are important mediators of hepatic ischemia-reperfusion injury.

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Richards, James A; Wigmore, Stephen J; Anderton, Stephen M; Howie, Sarah E M

2017-12-01

IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury. We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections. The absence of T cells (CD3εKO) is associated with significant protection from injury (p=0.010). Through a strategy of antibody depletion it appears that NKT cells (p=0.0025), rather than conventional T (CD4+ or CD8+) (p=0.11) cells that are the key mediators of injury. Our results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Penetrating Cardiac and Hepatic Injury; Polytrauma of a Child After Bombing

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Baris Akca

2013-10-01

Full Text Available After a bombing attack, patients were brought into hospital suffering from a combination of injuries caused by the blast, penetrating injuries and burns which as a case of polytrauma. In penetrating thoracoabdominal injuries due to bombing possibility of cardiac injury should be kept in mind. Penetrating cardiac injuries in children are rare but has a high mortality and morbidity. In some cases there may be difficulty in diagnosis of penetrating cardiac injury. In this case we want to share the diagnosis, treatment and follow-up processes of penetrating cardiac and hepatic injury with burns of a politrauma child due to bombing.

Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats.

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Fu-Chao Liu

Full Text Available Maraviroc is a CC-chemokine receptor 5 (CCR5 antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ-dependent pathway. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes, followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously with and without a PPAR(γ antagonist GW9662 (1 mg/kg, intravenously, GW9662 or vehicle was administered. Plasma alanine aminotransferase (ALT with aspartate aminotransferase (AST concentrations and various hepatic parameters were measured (n=8 rats/group at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ-dependent pathway.

Comparison of isolated and concomitant liver injuries: is hepatic trauma entirely responsible for the outcome?

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Yazici, P; Aydin, U; Sozbilen, M

2010-01-01

This study was undertaken to examine both isolated and concomitant liver injuries to clarify the role of liver trauma on outcome. This retrospective study was a review of all abdominal trauma patients who presented with liver injuries, with or without concomitant injury at Ege University School of Medicine over a 3-year period. Presentation, injury grade, management, and outcomes were analyzed. Patients with isolated hepatic injury (Group A) were compared with patients who had concomitant hepatic injury (liver and spleen/small bowel) (Group B). Significance was set at 95% confidence intervals. Of 368 patients, 80 (21%) presented with liver injury. Of these, the aetiology was as follows: 53 (66.2%) blunt injury, 19 (23%) penetrating injury, and 8 (10%) gun shot trauma. There were 38 patients in Group A and 42 in Group B. Of these 42 patients, 19 were diagnosed with serious types of injury ; eight thoracic, three open long bone fracture, one intra-cardiac, one intracranial. Six additional patients were observed with injuries to large abdominal vessels. Eleven patients (28.9%) with isolated hepatic injury were managed non-operatively. Mortality, intensive care unit and hospital length of stay, and transfusion requirements were significantly higher in Group B. Only the number of transfused blood units and the grade of liver injury were found to be effective on outcome whereas stepwise regression analysis revealed that injury type (penetrating) and blood transfusion were predictive for mortality. This study highlighted that although isolated liver injury results in good outcome with non-operative management, concomitant injuries to the liver lead to a higher failure and mortality rate. However, liver injury itself is rarely responsible for death.

Human neutrophil peptide-1 promotes alcohol-induced hepatic fibrosis and hepatocyte apoptosis.

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Rie Ibusuki

Full Text Available Neutrophil infiltration of the liver is a typical feature of alcoholic liver injury. Human neutrophil peptide (HNP-1 is an antimicrobial peptide secreted by neutrophils. The aim of this study was to determine if HNP-1 affects ethanol-induced liver injury and to examine the mechanism of liver injury induced by HNP-1.Transgenic (TG mice expressing HNP-1 under the control of a β-actin-based promoter were established. Ethanol was orally administered to HNP-1 TG or wild-type C57BL/6N (WT mice. SK-Hep1 hepatocellular carcinoma cells were used to investigate the effect of HNP-1 on hepatocytes in vitro.After 24 weeks of ethanol intake, hepatic fibrosis and hepatocyte apoptosis were significantly more severe in TG mice than in WT mice. Levels of CD14, TLR4, and IL-6 in liver tissues were higher in TG mice than in WT mice. Apoptosis was accompanied by higher protein levels of caspase-3, caspase-8, and cleaved PARP in liver tissue. In addition, phosphorylated ASK1, ASK1, phosphorylated JNK, JNK1, JNK2, Bax, Bak and Bim were all more abundant in TG mice than in WT mice. In contrast, the level of anti-apoptotic Bcl2 in the liver was significantly lower in TG mice than in WT mice. Analysis of microRNAs in liver tissue showed that miR-34a-5p expression was significantly higher in TG mice than in WT mice. Furthermore, in the presence of ethanol, HNP-1 increased the apoptosis with the decreased level of Bcl2 in a concentration-dependent manner in vitro.HNP-1 secreted by neutrophils may exacerbate alcohol-induced hepatic fibrosis and hepatocyte apoptosis with a decrease in Bcl2 expression and an increase in miR-34a-5p expression.

Lithium Carbonate in the Treatment of Graves’ Disease with ATD-Induced Hepatic Injury or Leukopenia

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Rendong Zheng

2015-01-01

Full Text Available Objective. GD with ATD-induced hepatic injury or leukopenia occurs frequently in clinical practice. The purpose of the present study was to observe the clinical effect of lithium carbonate on hyperthyroidism in patients with GD with hepatic injury or leukopenia. Methods. Fifty-one patients with GD with hepatic injury or leukopenia participated in the study. All patients were treated with lithium carbonate, in addition to hepatoprotective drugs or drugs that increase white blood cell count. Thyroid function, liver function, and white blood cells were measured. Clinical outcomes were observed after a 1-year follow-up. Results. After treatment for 36 weeks, symptoms of hyperthyroidism and the level of thyroid hormones were improved and liver function, and white blood cells returned to a normal level. Twelve patients (23.5% obtained clinical remission, 6 patients (11.8% relapsed after withdrawal, 25 patients (49.0% received radioiodine therapy, and 8 patients (15.7% underwent surgical procedures after lithium carbonate treatment. Conclusion. Lithium carbonate has effects on the treatment of mild-to-moderate hyperthyroidism caused by GD, and it is particularly suitable for patients with ATD-induced hepatic injury or leukopenia.

Computed tomography arterial portography for assessment of portal vein injury after blunt hepatic trauma.

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Fu, Chen Ju; Wong, Yon Cheong; Tsang, Yuk Ming; Wang, Li Jen; Chen, Huan Wu; Ku, Yi Kang; Wu, Cheng Hsien; Chen, Huan Wen; Kang, Shih Ching

2015-01-01

Intrahepatic portal vein injuries secondary to blunt abdominal trauma are difficult to diagnose and can result in insidious bleeding. We aimed to compare computed tomography arterial portography (CTAP), reperfusion CTAP (rCTAP), and conventional computed tomography (CT) for diagnosing portal vein injuries after blunt hepatic trauma. Patients with blunt hepatic trauma, who were eligible for nonoperative management, underwent CTAP, rCTAP, and CT. The number and size of perfusion defects observed using the three methods were compared. A total of 13 patients (seven males/six females) with a mean age of 34.5±14.1 years were included in the study. A total of 36 hepatic segments had perfusion defects on rCTAP and CT, while there were 47 hepatic segments with perfusion defects on CTAP. The size of perfusion defects on CT (239 cm3; interquartile range [IQR]: 129.5, 309.5) and rCTAP (238 cm3; IQR: 129.5, 310.5) were significantly smaller compared with CTAP (291 cm3; IQR: 136, 371) (both, P = 0.002). Perfusion defects measured by CTAP were significantly greater than those determined by either rCTAP or CT in cases of blunt hepatic trauma. This finding suggests that CTAP is superior to rCTAP and CT in evaluating portal vein injuries after blunt liver trauma.

Nuclear imaging of hepatic impact injury on rabbits

International Nuclear Information System (INIS)

Jin Rongbing; Wen Jianliang; Tang Weijia; Ma Xiaolin

2002-01-01

Objective: To investigate the effect and clinic application value of nuclear imaging on hepatic impact experiment. Methods: Experimental rabbits were impact injured on liver with BIM-IV bio-impact machine. Liver imaging was performed with sodium phytate labeled by 99m Tc. Liver blood pool imaging was performed with labeled red blood cells. The results of imaging were similar with the results of anatomy. Results: There were significant difference between normal liver and injured liver. Radio diminution and defect were showed on injured liver areas in labeled hepatic cells. Many types of abnormal radioactivity distribution were observed in liver pool imaging. The results of liver imaging and liver blood pool imaging were corresponded to the results of anatomy. Conclusion: Changes of hepatic cell structures and function after injury could be showed by nuclear imaging. Nuclear imaging was valuable in determining injured liver position or injured degree

Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats

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Nandini D.P.K. Manne

2017-07-01

Full Text Available Background: Hepatic ischemia reperfusion is one the main causes for graft failure following transplantation. Although, the molecular events that lead to hepatic failure following ischemia reperfusion (IR are diverse and complex, previous studies have shown that excessive formation of reactive oxygen species (ROS are responsible for hepatic IR injury. Cerium oxide (CeO2 nanoparticles have been previously shown to act as an anti-oxidant and anti-inflammatory agent. Here, we evaluated the protective effects of CeO2 nanoparticles on hepatic ischemia reperfusion injury. Methods: Male Sprague Dawley rats were randomly assigned to one of the four groups: Control, CeO2 nanoparticle only, hepatic ischemia reperfusion (IR group and hepatic ischemia reperfusion (IR plus CeO2 nanoparticle group (IR+ CeO2. Partial warm hepatic ischemia was induced in left lateral and median lobes for 1h, followed by 6h of reperfusion. Animals were sacrificed after 6h of reperfusion and blood and tissue samples were collected and processed for various biochemical experiments. Results: Prophylactic treatment with CeO2 nanoparticles (0.5mg/kg i.v (IR+CeO2 group 1 hour prior to hepatic ischemia and subsequent reperfusion injury lead to a decrease in serum levels of alanine aminotransaminase and lactate dehydrogenase at 6 hours after reperfusion. These changes were accompanied by significant decrease in hepatocyte necrosis along with reduction in several serum inflammatory markers such as macrophage derived chemokine, macrophage inflammatory protein-2, KC/GRO, myoglobin and plasminogen activator inhibitor-1. However, immunoblotting demonstrated no significant changes in the levels of apoptosis related protein markers such as bax, bcl2 and caspase 3 in IR and IR+ CeO2 groups at 6 hours suggesting necrosis as the main pathway for hepatocyte death. Conclusion: Taken together, these data suggest that CeO2 nanoparticles attenuate IR induced cell death and can be used as a prophylactic

Protection of the Extracts of Lentinus edodes Mycelia against Carbon-Tetrachloride-Induced Hepatic Injury in Rats

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Mei-Fen Chen

2012-01-01

Full Text Available Lentinus edodes is the medicinal macrofungus showing potential for therapeutic applications in infectious disorders including hepatitis. In an attempt to develop the agent for handling hepatic injury, we used the extracts of Lentinus edodes mycelia (LEM to screen the effect on hepatic injury in rats induced by carbon tetrachloride (CCl4. Intraperitoneal administration of CCl4 not only increased plasma glutamic oxaloacetic transaminase (GOT and glutamic pyruvic transaminase (GPT but also decreased hepatic superoxide dismutase (SOD and glutathione peroxidase (GPx levels in rats. Similar to the positive control silymarin, oral administration (three times daily of this product (LEM for 8 weeks significantly reduced plasma GOT and GPT. Also, the activities of antioxidant enzymes of SOD and GPx were elevated by LEM. in liver from CCl4-treated rats, indicating that mycelium can increase antioxidant-like activity. Moreover, the hepatic mRNA and protein levels of SOD and GPx were both markedly raised by LEM. The obtained results suggest that oral administration of the extracts of Lentinus edodes mycelia (LEM has the protective effect against CCl4-induced hepatic injury in rats, mainly due to an increase in antioxidant-like action.

Relation between blood clearance and hepatic uptake of sup 99m Tc-phytate in rats with hepatic injury

Energy Technology Data Exchange (ETDEWEB)

Shibata, Hiroshi; Hisano, Tomoyuki; Kohno, Masahiro (Yamaguchi University, Ube (Japan). Faculty of Agriculture)

1989-10-01

The relation among the blood clearance of {sup 99m}Tc-phytake ({sup 99m}Tc-P), the hepatic uptake of {sup 99m}Tc-P and the severity of hepatic injury was investigated by using the rats with carbon tetrachloride (CCL{sub 4}), D-galactosamine (Gal N), alpha-naphthylisothiocyanate (ANIT) or DL-ethionine (EthN) induced hepatic injury. After the administration of CCL{sub 4}, GalN or ANIT, serum GPT activity increased significantly with the increase of dose level, and the degree of this increase was in the order: GalN>CCl{sub 4}>ANIT. However, the mild increase in serum GPT activity was observed after EthN administration. The blood clearance rate of {sup 99m}Tc-P and the hepatic uptake ratio of {sup 99m}Tc-P decreased with the increase of dose level after CCl{sub 4}, GalN or ANIT administration, but significant changes were not found after EthN administration. The degree of decrease in the blood clearance rate of {sup 99m}Tc-P was in the order: GalNapproxCCl{sub 4}>ANIT, and the degree of decrease in the hepatic uptake ratio of {sup 99m}Tc-P was in the order: GalNapproxCCl{sub 4}>ANIT. These results suggest that the disorder in the hepatocytes may be one of causes for inducing the decrease in the hepatic uptake of {sup 99m}Tc-P, and the consequence of this decrease may induce the decrease in the blood clearance of {sup 99m}Tc-P. (author).

Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

KAUST Repository

Diaz Rua, Ruben

2017-04-19

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

KAUST Repository

Diaz Rua, Ruben; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M.; Oliver, Paula

2017-01-01

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats.

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Díaz-Rúa, Rubén; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M; Oliver, Paula

2017-08-01

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid-base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid-base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences. Copyright © 2017 Elsevier Inc. All rights reserved.

Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy

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Miao Shen

2013-01-01

Full Text Available Background. Hepatic ischemia-reperfusion (I/R injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg were administered 1 h before a model of segmental (70% hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h. Results. Alanine aminotransferase (ALT, aspartate aminotransferase (AST, and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg. The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg. Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6. Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.

Study on pretreatment of FPS-1 in rats with hepatic ischemia-reperfusion injury.

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Lin, Shiqing; Liu, Kexuan; Wu, Weikang; Chen, Chao; Wang, Zhi; Zhang, Xuanhong

2009-01-01

This study was designed to determine whether FPS-1, the water-soluble polysaccharide isolated from fuzi, protected against hepatic damage in hepatic ischemia-reperfusion injury in rats, and its mechanism. SD rats were subjected to 60 min of hepatic ischemia, followed by 120 min reperfusion. FPS-1 (160 mg/kg/day) was administered orally for 5 days before ischemia-reperfusion injury in treatment group. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (ALB) were assayed to evaluate liver functions. Liver samples were taken for histological examination and determination of malondialdehyde (MDA), superoxide dismutase (SOD), that catalase (CAT) in liver. Na(+)-K(+)-ATPase and Ca(2+)-ATPase in mitochondria were measured with colorimetry method. Morphological changes were also investigated by using both light microscopy and electron microscopy (EM). In addition, apoptosis and oncosis were detected by Annexin V-FITC/PI immunofluorescent flow cytometry analysis. Serum AST and ALT levels were elevated in groups exposed to ischemia-reperfusion (p FPS-1 reversed all these biochemical parameters as well as histological alterations, evidently by increased SOD, CAT, reduced MDA and histological scores compared to the model group (p FPS-1 could attenuate the necrotic states by the detection of immunofluorescent flow cytometry analysis. Pretreatment with FPS-1 reduced hepatic ischemia-reperfusion injury through its potent antioxidative effects and attenuation of necrotic states.

The G-250A polymorphism in the hepatic lipase gene promoter is associated with changes in hepatic lipase activity and LDL cholesterol: The KANWU Study

DEFF Research Database (Denmark)

Lindi, Virpi; Schwab, Ursula; Louheranta, Anne

2007-01-01

BACKGROUND AND AIMS: Hepatic lipase (HL) catalyzes the hydrolysis of triglycerides and phospholipids from lipoproteins, and promotes the hepatic uptake of lipoproteins. A common G-250A polymorphism in the promoter of the hepatic lipase gene (LIPC) has been described. The aim was to study...

Concomitant injuries are an important determinant of outcome of high-grade blunt hepatic trauma.

Science.gov (United States)

Schnüriger, B; Inderbitzin, D; Schafer, M; Kickuth, R; Exadaktylos, A; Candinas, D

2009-01-01

Little is known about the clinical importance of concomitant injuries in polytraumatized patients with high-grade blunt liver injury. A retrospective single-centre study was performed to investigate the safety of non-operative management of liver injury and the impact of concomitant intra- and extra-abdominal injuries on clinical outcome. Some 183 patients with blunt liver injury were admitted to Berne University Hospital, Switzerland, between January 2000 and December 2006. Grade 3-5 injuries were considered to be high grade. Immediate laparotomy was required by 35 patients (19.1 per cent), owing to extrahepatic intra-abdominal injury (splenic and vascular injuries, perforations) in 21 cases. The mortality rate was 16.9 per cent; 22 of the 31 deaths were due to concomitant lesions. Of 81 patients with high-grade liver injury, 63 (78 per cent) were managed without surgery; liver-related and extra-abdominal complication rates in these patients were 11 and 17 per cent respectively. Grades 4 and 5 liver injury were associated with hepatic-related and extra-abdominal complications. Concomitant injuries are a major determinant of outcome in patients with blunt hepatic injury and should be given high priority by trauma surgeons. An algorithm for the management of blunt liver injury is proposed. Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Right hepatic vein injury after blunt abdominal trauma in a 12-year-old boy- case report

International Nuclear Information System (INIS)

Roik, D.; Konecka, A.; Brzewski, M.; Marcinski, A.; Kaminski, A.; Piotrowska, A.; Jasinska, A.

2008-01-01

Blunt abdominal trauma in children is one of the most frequent causes of hospitalization. We present a rare case of traumatic liver injury. A 12-year-old boy was admitted to the Surgery Department after a bicycle fall and handlebar impact injury to the right infracostal area. At admission he was stable, with no abnormalities except for a subcutaneous hepatoma found in the injured area. Abdominal ultrasound examination revealed free intraperitoneal fluid. Computed tomography (CT) revealed irregular branching laceration of the right superior hepatic segments with extension into the hepatic veins. No active extravasation of contrast material was seen. On the next day, cause of the deterioration of the patient's condition, CT examination was repeated and revealed focal extravasation of contrast material in the portal hilum posterior to the gallbladder. An injury of the right hepatic vein was found on laparotomy. Hepatic vein injury is a rare but very serious complication after blunt liver trauma and it is an indication for surgical treatment. Diagnostic imaging is essential for therapeutic decisions, but its value is sometimes limited.The precise analysis of injury mechanism and localization may be very helpful.CT is currently the modality of choice for the evaluation of blunt liver trauma. If an active bleeding is suspected the delayed scans seem to be recommended. (author)

Saccharomyces boulardii prevention of the hepatic injury induced by Salmonella Enteritidis infection.

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Wu, Daichao; Teng, Da; Wang, Xiumin; Dai, Changsong; Wang, Jianhua

2014-10-01

Salmonella enterica subsp. enterica serovar Enteritidis (Salmonella Enteritidis) is the predominant cause of serovar-associated food-borne outbreaks in many countries and causes significant clinical symptoms of liver injury, enteritis, and diarrheal diseases. Saccharomyces boulardii is used in clinical application for prophylaxis and the treatment of a variety of diseases caused by bacterial infection. We used a mouse model of Salmonella Enteritidis infection, which included pretreatment with S. boulardii, to reveal the protection mechanisms of S. boulardii against Salmonella Enteritidis infection, including the translocation of Salmonella Enteritidis to the liver 10 days after Salmonella Enteritidis challenge, and the colonisation of Salmonella Enteritidis and the formation of hepatic tissue lesions in mice after Salmonella Enteritidis challenge on the 10th day. Compared with Salmonella Enteritidis infection in mice, S. boulardii decreased Salmonella Enteritidis translocation to the liver by 96%, and 99% of Salmonella Enteritidis colonised the cecum on the 10th day. Saccharomyces boulardii also abated hepatic tissue injury caused by the infiltration of neutrophilic granulocytes, lymphocytes, and plasmocytes by decreasing the translocation of Salmonella to the liver. These findings demonstrated that S. boulardii is an effective agent in the prevention of the hepatic injury induced by Salmonella Enteritidis infection in a mouse model.

Isolated Right Segmental Hepatic Duct Injury Following Laparoscopic Cholecystectomy

International Nuclear Information System (INIS)

Perini, Rafael F.; Uflacker, Renan; Cunningham, John T.; Selby, J. Bayne; Adams, David

2005-01-01

Purpose. Laparoscopic cholecystectomy (LC) is the treatment of choice for gallstones. There is an increased incidence of bile duct injuries in LC compared with the open technique. Isolated right segmental hepatic duct injury (IRSHDI) represents a challenge not only for management but also for diagnosis. We present our experience in the management of IRSHDI, with long-term follow-up after treatment by a multidisciplinary approach. Methods. Twelve consecutive patients (9 women, mean age 48 years) were identified as having IRSHDI. Patients' demographics, clinical presentation, management and outcome were collected for analysis. The mean follow-up was 44 months (range 2-90 months). Results. Three patients had the LC immediately converted to open surgery without repair of the biliary injury before referral. Treatments before referral included endoscopic retrograde cholangiopancreatography (ERCP), percutaneous drainage and surgery, isolated or in combination. The median interval from LC to referral was 32 days. Eleven patients presented with biliary leak and biloma, one with obstruction of an isolated right hepatic segment. Post-referral management of the biliary lesion used a combination of ERCP stenting, percutaneous drainage and stent placement and surgery. In 6 of 12 patients ERCP was the first procedure, and in only one case was IRSHDI identified. In 6 patients, percutaneous transhepatic cholangiography (PTC) was performed first and an isolated right hepatic segment was demonstrated in all. The final treatment modality was endoscopic management and/or percutaneous drainage and stenting in 6 patients, and surgery in 6. The mean follow-up was 44 months. No mortality or significant morbidity was observed. Conclusion. Successful management of IRSHDI after LC requires adequate identification of the lesion, and multidisciplinary treatment is necessary. Half of the patients can be treated successfully by nonsurgical procedures

Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation.

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Hsu, Jun-Te; Kan, Wen-Hong; Hsieh, Chi-Hsun; Choudhry, Mashkoor A; Schwacha, Martin G; Bland, Kirby I; Chaudry, Irshad H

2007-10-01

Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)-1. Up-regulation of HO-1 mediates potent, anti-inflammatory effects and attenuates organ injury. Although studies have shown that 17beta-estradiol (E2) prevents organ damage following trauma-hemorrhage, it remains unknown whether Akt/HO-1 plays any role in E2-mediated attenuation of hepatic injury following trauma-hemorrhage. To study this, male rats underwent trauma-hemorrhage (mean blood pressure, approximately 40 mmHg for 90 min), followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body weight), E2 plus the PI-3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma-hemorrhage, plasma alpha-GST and hepatic tissue myeloperoxidase (MPO) activity, IL-6, TNF-alpha, ICAM-1, cytokine-induced neutrophil chemoattractant-1, and MIP-2 levels were measured. Hepatic Akt and HO-1 protein levels were also determined. Trauma-hemorrhage increased hepatic injury markers (alpha-GST and MPO activity), cytokines, ICAM-1, and chemokine levels. These parameters were markedly improved in the E2-treated rats following trauma-hemorrhage. E2 treatment also increased hepatic Akt activation and HO-1 expression compared with vehicle-treated, trauma-hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma-hemorrhage are in part mediated via an ER-related, Akt-dependent up-regulation of HO-1.

Application of radionuclide imaging to hepatic impact injury in rabbits

Institute of Scientific and Technical Information of China (English)

金榕兵; 麻晓林; 温建良; 唐维佳

2004-01-01

Objective: To investigate the role and clinical value of radionuclide imaging in hepatic impact injuries in rabbits.Methods: Rabbits were experimentally impacted on the liver with BIM-IV bio-impact machine. Liver imaging was performed with 99mTc labeled sodium phytate. Liver blood pool imaging was performed with 99mTc -stannous pyrophosphate labeled red blood cells. The results of radionuclide imaging were compared with the anatomic results.Results: There was significant difference between the images of the injured liver and the control. Radio diminution and defect were shown in the injured liver areas. Various sorts of abnormal radioactivity distribution were observed with hepatic blood pool imaging. The results of the liver imaging and liver blood pool imaging were accorded with the results of the anatomic findings.Conclusions: Radionuclide imaging may well display the changes of hepatocellular structures and functions after injury, which is valuable in locating the concrete injured position and differentiating the injured degrees of liver.

Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation.

Science.gov (United States)

Griffeth, L K; Rosen, G M; Rauckman, E J

1985-01-01

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.

Phytosterols Promote Liver Injury and Kupffer Cell Activation in Parenteral Nutrition–Associated Liver Disease

Science.gov (United States)

El Kasmi, Karim C.; Anderson, Aimee L.; Devereaux, Michael W.; Vue, Padade M.; Zhang, Wujuan; Setchell, Kenneth D. R.; Karpen, Saul J.; Sokol, Ronald J.

2014-01-01

Parenteral nutrition–associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)–based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD. PMID:24107776

Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia-Reperfusion Injury

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Huili Li

2016-01-01

Full Text Available Hepatic ischemia-reperfusion (I/R injury is a serious complication in clinical practice. However, no efficient biomarkers are available for the evaluation of the severity of I/R injury. Recently, renalase has been reported to be implicated in the I/R injury of various organs. This protein is secreted into the blood in response to increased oxidative stress. To investigate the responsiveness of renalase to oxidative stress, we examined the changes of renalase in cell and mouse models. We observed a significant increase of renalase expression in HepG2 cells in a time- and dose-dependent manner when treated with H2O2. Renalase expression also increased significantly in liver tissues that underwent the hepatic I/R process. The increased renalase levels could be efficiently suppressed by antioxidants in vitro and in vivo. Furthermore, serum renalase levels were significantly increased in the mouse models and also efficiently suppressed by antioxidants treatment. The variation trends are consistent between renalase and liver enzymes in the mouse models. In conclusion, renalase is highly sensitive and responsive to oxidative stress in vitro and in vivo. Moreover, renalase can be detected in the blood. These properties make renalase a highly promising biomarker for the evaluation of the severity of hepatic I/R injury.

Hepatic parenchymal atrophy induction for intractable segmental bile duct injury after liver resection.

Science.gov (United States)

Hwang, Shin; Park, Gil-Chun; Ha, Tae-Yong; Ko, Gi-Young; Gwon, Dong-Il; Choi, Young-Il; Song, Gi-Won; Lee, Sung-Gyu

2012-05-01

Liver resection can result in various types of bile duct injuries but their treatment is usually difficult and often leads to intractable clinical course. We present an unusual case of hepatic segment III duct (B3) injury, which occurred after left medial sectionectomy for large hepatocellular carcinoma and was incidentally detected 1 week later due to bile leak. Since the pattern of this B3 injury was not adequate for operative biliary reconstruction, atrophy induction of the involved hepatic parenchyma was attempted. This treatment consisted of embolization of the segment III portal branch to inhibit bile production, induction of heavy adhesion at the bile leak site and clamping of the percutaneous transhepatic biliary drainage (PTBD) tube to accelerate segment III atrophy. This entire procedure, from liver resection to PTBD tube removal took 4 months. This patient has shown no other complication or tumor recurrence for 4 years to date. These findings suggest that percutaneous segmental portal vein embolization, followed by intentional clamping of external biliary drainage, can effectively control intractable bile leak from segmental bile duct injury.

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben; Van Schothorst, E. M.; Keijer, J.; Palou, A.; Oliver, P.

2016-01-01

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben

2016-03-22

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury.

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Kim, Jin Yong; Lee, Dong Yun; Kang, Sukmo; Miao, Wenjun; Kim, Hyungjun; Lee, Yonghyun; Jon, Sangyong

2017-07-01

Hepatic ischemia-reperfusion injury (IRI) remains a major concern in liver transplantation and resection, despite continuing efforts to prevent it. Accumulating evidence suggests that bilirubin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. We recently developed bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol (PEG)-conjugated bilirubin. Here, we sought to investigate whether BRNPs protect against IRI in the liver by preventing oxidative stress. BRNPs exerted potent antioxidant and anti-apoptotic activity in primary hepatocytes exposed to hydrogen peroxide, a precursor of reactive oxygen species (ROS). In a model of hepatic IRI in mice, BRNP preconditioning exerted profound protective effects against hepatocellular injury by reducing oxidative stress, pro-inflammatory cytokine production, and recruitment of neutrophils. They also preferentially accumulated in IRI-induced inflammatory lesions. Collectively, our findings indicate that BRNP preconditioning provides a simple and safe approach that can be easily monitored in the blood like endogenous bilirubin, and could be a promising strategy to protect against IRI in a clinical setting. Copyright © 2017 Elsevier Ltd. All rights reserved.

Management of adult blunt hepatic trauma.

Science.gov (United States)

Kozar, Rosemary A; McNutt, Michelle K

2010-12-01

To review the nonoperative and operative management of blunt hepatic injury in the adult trauma population. Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to a patient at increased risk of hepatic complications following nonoperative management. Blunt hepatic injury remains a frequent intraabdominal injury in the adult trauma population. The management of blunt hepatic injury has undergone a major paradigm shift from mandatory operative exploration to nonoperative management. Hemodynamic instability with a positive focused abdominal sonography for trauma and peritonitis are indications for emergent operative intervention. Although surgical intervention for blunt hepatic trauma is not as common as in years past, it is imperative that the current trauma surgeon be familiar with the surgical skill set to manage complex hepatic injuries. This study represents a review of both nonoperative and operative management of blunt hepatic injury.

Primary hepatic artery embolization in pediatric blunt hepatic trauma.

Science.gov (United States)

Ong, Caroline C P; Toh, Luke; Lo, Richard H G; Yap, Te-Lu; Narasimhan, Kannan

2012-12-01

Non-operative management of isolated blunt hepatic trauma is recommended except when hemodynamic instability requires immediate laparotomy. Hepatic artery angioembolization is increasingly used for hepatic injuries with ongoing bleeding as demonstrated by contrast extravasation on the CT scan. It is used primarily or after laparotomy to control ongoing hemorrhage. Hepatic angioembolization as part of multimodality management of hepatic trauma is reported mainly in adults, with few pediatric case reports. We describe our institution experience with primary pediatric hepatic angioembolization and review the literature with regard to indications and complications. Two cases (3 and 8 years old), with high-grade blunt hepatic injuries with contrast extravasation on the CT scan were successfully managed by emergency primary hepatic angioembolization with minimal morbidity and avoided laparotomy. To date, the only reports of pediatric hepatic angioembolization for trauma are 5 cases for acute bleeding and 15 delayed cases for pseudoaneurysm. The role of hepatic angioembolization in the presence of an arterial blush on CT in adults is accepted, but contested in a pediatric series, despite higher transfusion rate and mortality rate. We propose that hepatic angioembolization should be considered adjunct treatment, in lieu of, or in addition to emergency laparotomy for hemostasis in pediatric blunt hepatic injury. Copyright © 2012 Elsevier Inc. All rights reserved.

Amelioration of carbon tetrachloride-induced hepatic injury by emulsified Antrodia extract

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Wei-Chih Chang

2018-03-01

Full Text Available Objective(s: Antrodia cinnamomea (AC is found with anti-inflammatory and immunomodulatory biological activities. In this study, we investigated the anti-hepatitis effect of the emulsified AC extract from RO water or supercritical fluid CO2 with ethanol co-solvent extract methods of AC preparations. Materials and Methods: Five groups of eight to ten weeks male rats with a count of ten for each group were studied to evaluate the protection of two kinds of AC extract from hepatic injury. Acute liver injury of rats was induced by injecting 40% carbon tetrachloride (CCl4 1 mg/kg intraperitoneally. Positive and negative control groups rats were perfused with CCl4 or isotonic saline, respectively. Experimental groups received oral administration once/day of AC preparations before CCl4 treatment: water AC extract (WAE group, or emulsified AC extract from supercritical fluid extraction (EAE group for 5 days, and sacrificed on the 6th day and the blood and liver samples were collected under chloral hydrate anesthesia. The anti-inflammatory, antioxidant markers, and relevant signaling pathways were measured (AST, ALT, ROS, IL-1, IL-6, NO, and COX-2, MAPKs, and caspase-3. Results: EAE at 50 mg/kg significantly decreased the serum AST, ALT, IL-1, IL-6, NO, and ROS levels. Both extracts reduced the activation of p-ERK in the liver samples, but EAE inhibited COX-2 and caspase-3 protein expression better than WAE. The EAE ameliorated CCl4-induced hepatic injury significantly; as compared with WAE and the positive control. Conclusion: The hepatoprotection of EAE could be attributed to the antioxidant and anti-inflammatory effects of Antrodia.

Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.

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Alexander Wehr

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH, fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20, confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4- and chronic methionine-choline-deficient (MCD diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

African Safety Promotion: A Journal of Injury and Violence Prevention

African Journals Online (AJOL)

African Safety Promotion: A Journal of Injury and Violence Prevention (ASP) is a forum for discussion and debate among scholars, policy-makers and practitioners active in the field of injury prevention and safety promotion. ASP seeks to promote research and dialogue around a central public health issue that affects Africa, ...

Preventive activity of banana peel polyphenols on CCl4-induced experimental hepatic injury in Kunming mice.

Science.gov (United States)

Wang, Rui; Feng, Xia; Zhu, Kai; Zhao, Xin; Suo, Huayi

2016-05-01

The aim of the present study was to evaluate the preventive effects of banana peel polyphenols (BPPs) against hepatic injury. Mice were divide into normal, control, 100 mg/kg and 200 mg/kg banana peel polyphenol and silymarin groups. All the mice except normal mice were induced with hepatic damage using CCl 4 . The serum and tissue levels of mice were determined by a kit and the tissues were further examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. BPPs reduced the serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase in a CCl 4 -induced mouse model of hepatic injury. Furthermore, BPPs reduced the levels of malondialdehyde and triglyceride, while increasing glutathione levels in the serum and liver tissues of mice. In addition, the effects of 200 mg/kg treatment were more evident, and these effects were comparable to those of the drug silymarin. Serum levels of the cytokines, interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon-γ, were reduced in the mice treated with BPPs compared with injury control group mice, and these levels were comparable to those of the normal and silymarin-treated groups. Histopathological examination indicated that BPPs were able to reduce the extent of CCl 4 -induced liver tissue injury and protect the liver cells. Furthermore, the mRNA and protein expression levels of the inflammation-associated factors cyclooxygenase-2, nitric oxide synthase, TNF-α and IL-1β were reduced in mice treated with BPPs compared with the control group mice. Mice that received 200 mg/kg BPP exhibited reduced expression levels of these factors compared with mice that received 100 mg/kg BPP. In conclusion, the results of the present study suggested that BPPs exert a good preventive effect against hepatic injury.

The role of Aboriginal community attachment in promoting lifestyle changes after hepatitis C diagnosis

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Loren Brener

2015-08-01

Full Text Available This research assessed whether greater attachment to an Aboriginal community buffers against the negative effects of stigma and promotes positive health outcomes. Aboriginal Australians ( n  = 203 living with hepatitis C completed a survey assessing community attachment, stigma, resilience, quality of life, treatment intent, hepatitis C knowledge and positive lifestyle changes. A stronger sense of community attachment was associated with greater resilience, increased quality of life, less hepatitis C–related stigma and with increased lifestyle changes after diagnosis. Hence, community attachment can buffer against the negative health effects of stigma and may promote the resources to engage in positive behaviour changes, ultimately increasing long-term health outcomes.

Mechanism of salutary effects of astringinin on rodent hepatic injury following trauma-hemorrhage: Akt-dependent hemeoxygenase-1 signaling pathways.

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Liu, Fu-Chao; Hwang, Tsong-Long; Lau, Ying-Tung; Yu, Huang-Ping

2011-01-01

Astringinin can attenuate organ injury following trauma-hemorrhage, the mechanism remains unknown. Protein kinase B/hemeoxygenase-1 (Akt/HO-1) pathway exerts potent anti-inflammatory effects in various tissues. The aim of this study is to elucidate whether Akt/HO-1 plays any role in astringinin-mediated attenuation of hepatic injury following trauma-hemorrhage. For study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 35-40 mmHg for 90 min) followed by fluid resuscitation. A single dose of astringinin (0.3 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or a HO antagonist (chromium-mesoporphyrin) was administered during resuscitation. Various parameters were measured at 24 h post-resuscitation. Results showed that trauma-hemorrhage increased plasma aspartate and alanine aminotransferases (AST and ALT) concentrations and hepatic myeloperoxidase activity, cytokine induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1, and interleukin-6 levels. These parameters were significantly improved in the astringinin-treated rats subjected to trauma-hemorrhage. Astringinin treatment also increased hepatic Akt activation and HO-1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of wortmannin or chromium-mesoporphyrin abolished the astringinin-induced beneficial effects on post-resuscitation pro-inflammatory responses and hepatic injury. These findings collectively suggest that the salutary effects of astringinin administration on attenuation of hepatic injury after trauma-hemorrhage are likely mediated via Akt dependent HO-1 up-regulation.

Hepatic pseudoaneurysm after traumatic liver injury; is CT follow-up warranted?

DEFF Research Database (Denmark)

Østerballe, Lene; Helgstrand, Frederik; Axelsen, Thomas

2014-01-01

INTRODUCTION: Hepatic pseudoaneurysm (HPA) is a rare complication after liver trauma, yet it is potentially fatal, as it can lead to sudden severe haemorrhage. The risk of developing posttraumatic HPA is one of the arguments for performing follow-up CT of patients with liver injuries. The aim...... no treatment failures. There was no correlation between the severity of the liver injury and development of HPA. 5 out of 7 patients were asymptomatic and would have been discharged without treatment if the protocol did not include a default follow-up CT. CONCLUSIONS: In conclusion, this study shows that HPA...

Operative management and outcomes in 103 AAST-OIS grades IV and V complex hepatic injuries: trauma surgeons still need to operate, but angioembolization helps.

Science.gov (United States)

Asensio, Juan A; Roldán, Gustavo; Petrone, Patrizio; Rojo, Esther; Tillou, Areti; Kuncir, Eric; Demetriades, Demetrios; Velmahos, George; Murray, James; Shoemaker, William C; Berne, Thomas V; Chan, Linda

2003-04-01

American Association for the Surgery of Trauma (AAST) Organ Injury Scale (OIS) grades IV and V complex hepatic injuries are highly lethal. Our objectives were to review experience and identify predictors of outcome and to evaluate the role of angioembolization in decreasing mortality. This was a retrospective 8-year study of all patients sustaining AAST-OIS grades IV and V hepatic injuries managed operatively. Statistical analysis was performed using univariate and multivariate logistic regression. The main outcome measure was survival. The study included 103 patients, with a mean Revised Trauma Score of 5.61 +/- 2.55 and a mean Injury Severity Score of 33 +/- 9.5. Mechanism of injury was penetrating in 80 (79%) and blunt in 23 (21%). Emergency department thoracotomy was performed in 21 (25%). AAST grade IV injuries occurred in 51 (47%) and grade V injuries occurred in 52 (53%). Mean estimated blood loss was 9,414 mL. Overall survival was 43%. Adjusted overall survival rate after emergency department thoracotomy patients were excluded was 58%. Results stratified to AAST-OIS injury grade were as follows: grade IV, 32 of 51 (63%); grade V, 12 of 52 (23%); grade IV versus grade V (p Trauma Score (adjusted p hepatic veins (adjusted p hepatic injuries.

TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in MiceSummary

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Ling Yang

2017-05-01

Full Text Available Background & Aims: Toll-like receptor 4 (TLR4 signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF. TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis. Methods: A choline-deficient amino acid defined (CDAA diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined. Results: In the CDAA diet–induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1 and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury. Conclusions: In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic

Augmented hepatic injury followed by impaired regeneration in metallothionein-I/II knockout mice after treatment with thioacetamide

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Oliver, Jordan R.; Jiang, Sean; Cherian, M. George

2006-01-01

A previous study (Oliver, J.R., Mara, T.W., Cherian, M.G. 2005. Impaired hepatic regeneration in metallothionein-I/II knockout mice after partial hepatectomy. Exp. Biol. Med. 230, 61-67) has shown an impairment of liver regeneration following partial hepatectomy (PH) in metallothionein (MT)-I and MT-II gene knockout (MT-null) mice, thus suggesting a requirement for MT in cellular growth. The present study was undertaken to investigate whether MT may play a similar role in hepatic injury and regeneration after acute treatment with thioacetamide (TAA). Hepatotoxicity of TAA is caused by the generation of oxidative stress. TAA was injected ip to both wild-type (WT) and MT-null mice. Mice were killed at 6, 12, 24, 48, 60, and 72 h after injection of TAA (125 mg/kg) or 48 h after injection of saline (vehicle control), and different parameters of hepatic injury were measured. The levels of hepatic lipid peroxidation were increased at 12 h in both types of mice; however, lipid peroxidation was significantly less in WT mice than MT-null mice at 48 h after injection of TAA. Analysis of hepatic glutathione (GSH) levels after TAA injection showed depletion of GSH at 12 h in WT mice and at 6 h in MT-null mice; however, significantly more GSH was depleted early (6-24 h) in MT-null mice than WT mice. An increase in hepatic iron (Fe) levels was observed in both types of mice after injection of TAA, but Fe levels were significantly higher in MT-null mice than WT mice at 6-60 h. The levels of hepatic copper (Cu) and zinc (Zn) were significantly higher in WT mice than MT-null mice at 6-60 h for Cu, and at 24 h and 60 h for Zn, respectively. Histopathological examination showed hemorrhagic necrosis in the liver of both types of mice at 12-72 h, with hepatic injury being more prominent in MT-null mice than WT mice. The hepatic MT levels were increased in WT mice after injection of TAA, and were highest at 24-72 h. Immunohistochemical staining for MT in WT mice indicated the presence

Hyperglycemia Aggravates Hepatic Ischemia Reperfusion Injury by Inducing Chronic Oxidative Stress and Inflammation

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Yihan Zhang

2016-01-01

Full Text Available Aim. To investigate whether hyperglycemia will aggravate hepatic ischemia reperfusion injury (HIRI and the underlying mechanisms. Methods. Control and streptozotocin-induced diabetic Sprague-Dawley rats were subjected to partial hepatic ischemia reperfusion. Liver histology, transferase, inflammatory cytokines, and oxidative stress were assessed accordingly. Similarly, BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R after high (25 mM or low (5.5 mM glucose culture. Cell viability, reactive oxygen species (ROS, and activation of nuclear factor-erythroid 2-related factor 2 (Nrf2 and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB were determined. Results. Compared with control, diabetic rats presented more severe hepatic injury and increased hepatic inflammatory cytokines and oxidative stress. HIRI in diabetic rats could be ameliorated by pretreatment of N-acetyl-L-cysteine (NAC or apocynin. Excessive ROS generation and consequent Nrf2 and NF-κB translocation were determined after high glucose exposure. NF-κB translocation and its downstream cytokines were further increased in high glucose cultured group after H/R. While proper regulation of Nrf2 to its downstream antioxidases was observed in low glucose cultured group, no further induction of Nrf2 pathway by H/R after high glucose culture was identified. Conclusion. Hyperglycemia aggravates HIRI, which might be attributed to chronic oxidative stress and inflammation and potential malfunction of antioxidative system.

Physicochemical properties, antioxidant activities and protective effect against acute ethanol-induced hepatic injury in mice of foxtail millet (Setaria italica) bran oil.

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Pang, Min; He, Shujian; Wang, Lu; Cao, Xinmin; Cao, Lili; Jiang, Shaotong

2014-08-01

This study was designed to investigate physicochemical characterization of the oil extracted from foxtail millet bran (FMBO), and the antioxidant and hepatoprotective effects against acute ethanol-induced hepatic injury in mice. GC-MS analysis revealed that unsaturated fatty acids (UFAs) account for 83.76% of the total fatty acids; in particular, the linoleic acid (C18:2) is the predominant polyunsaturated fatty acid (PUFA), and the compounds of squalene and six phytosterols (or phytostanols) were identified in unsaponifiable matter of FMBO. The antioxidant activity examination of FMBO in vitro showed highly ferric-reducing antioxidant power and scavenging effects against DPPH· and HO· radicals. Furthermore, the protective effect of FMBO against acute hepatic injuries induced by ethanol was verified in mice. In this, intragastric administration with different dosages of FMBO in mice ahead of acute ethanol administration could observably antagonize the ethanol-induced increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and the hepatic malondialdehyde (MDA) levels, respectively, along with enhanced hepatic superoxide dismutase (SOD) levels relative to the control. Hepatic histological changes were also observed and confirmed that FMBO is capable of attenuating ethanol-induced hepatic injury.

Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury

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Yin Hui; Huang Baojun; Yang Heng; Huang Yafei; Xiong Ping; Zheng Fang; Chen Xiaoping; Chen Yifa; Gong Feili

2006-01-01

The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-α and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-κB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway

Huperzine A attenuates hepatic ischemia reperfusion injury via anti-oxidative and anti-apoptotic pathways.

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Xu, Zhe; Wang, Yang

2014-08-01

Hepatic ischemia reperfusion (HI/R) injury may occur during liver transplantation and remains a serious concern in clinical practice. Huperzine A (HupA), an alkaloid isolated from the Chinese traditional medicine Huperzia serrata, has been demonstrated to possess anti‑oxidative and anti‑apoptotic properties. In the present study, a rat model of HI/R was established by clamping the hepatic artery, the hepatoportal vein and the bile duct with a vascular clamp for 30 min followed by reperfusion for 6 h under anesthesia. HupA was injected into the tail vein 5 min prior to the induction of HI/R at doses of 167 and 500 µg/kg. The histopathological assessment of the liver was performed using hematoxylin and eosin staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed in the serum samples. The tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA) and glutathione (GSH) were also measured spectrophotometrically. Furthermore, the protein expression of caspase‑3, Bcl‑2 and Bax in hepatic tissues was detected via western blot analysis. Treatment of Wistar rats with HupA at doses of 167 and 500 µg/kg markedly attenuated HI/R injury as observed histologically. In addition, the significant reductions of serum ALT and AST were observed in HupA‑treated ischemic rats. Furthermore, HupA treatment enhanced the activity of hepatic tissue SOD, CAT and GSH, but decreased the MDA tissue content. Western blot analysis revealed elevated levels of Bcl‑2 expression but decreased Bax and caspase‑3 tissue expression at the protein level in the HupA‑treated group. The present data suggest that HupA attenuates the HI/R injury of rats through its anti‑oxidative and anti‑apoptotic signaling pathways.

Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

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Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

2014-01-08

Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

[The effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion in a rabbit model].

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Wang, Ye; Yang, Jia-mei; Hou, Yuan-kai; Li, Dian-qi; Hu, Ming-hua; Liu, Peng

2008-04-15

To investigate the effect and mechanism of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion. A rabbit hepatic ischemia reperfusion injury model was established by hepatic portal occlusion and in situ hypothermic irrigation for 30 min. Twenty-four New Zealand white rabbits were employed and randomly divided into 3 groups equally by different dosage of portal blood stasis removal: group A5 (5 ml blood removal), group A10 (10 ml blood removal),and group B (no blood removal). Eight rabbits were served as controls with no hepatic portal occlusion and hypothermic irrigation. After reperfusion 4 h serum endotoxin content, tumor necrosis factor-alpha (TNF-alpha), urea nitrogen (BUN), and creatinine (Cr) were examined respectively, meantime lung and kidney tissues were sampled to determine the content of malondialdehyde (MDA), superoxide dismutase (SOD), the pathology, and wet to dry weight ratio, broncho-alveolar lavage fluid protein content in lung tissues. Removing portal blood stasis ameliorated lung and renal injury as shown by decreasing the level of serum endotoxin, TNF-alpha, BUN, Cr, wet to dry weight ratio, broncho-alveolar lavage fluid protein content, MDA, SOD. TNF-alpha, Cr, broncho-alveolar lavage fluid protein content in lung tissues and MDA in kidney tissue in group A5 were significantly reduced compared with those in group B (P portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion. The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption, and further decreases production of serum TNF-alpha.

Evolving Role of Endoscopic Retrograde Cholangiopancreatography in Management of Extrahepatic Hepatic Ductal Injuries due to Blunt Trauma: Diagnostic and Treatment Algorithms

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Nikhil P. Jaik

2008-01-01

Full Text Available Extrahepatic hepatic ductal injuries (EHDIs due to blunt abdominal trauma are rare. Given the rarity of these injuries and the insidious onset of symptoms, EHDI are commonly missed during the initial trauma evaluation, making their diagnosis difficult and frequently delayed. Diagnostic modalities useful in the setting of EHDI include computed tomography (CT, abdominal ultrasonography (AUS, nuclear imaging (HIDA scan, and cholangiography. Traditional options in management of EHDI include primary ductal repair with or without a T-tube, biliary-enteric anastomosis, ductal ligation, stenting, and drainage. Simple drainage and biliary decompression is often the most appropriate treatment in unstable patients. More recently, endoscopic retrograde cholangiopancreatography (ERCP allowed for diagnosis and potential treatment of these injuries via stenting and/or papillotomy. Our review of 53 cases of EHDI reported in the English-language literature has focused on the evolving role of ERCP in diagnosis and treatment of these injuries. Diagnostic and treatment algorithms incorporating ERCP have been designed to help systematize and simplify the management of EHDI. An illustrative case is reported of blunt traumatic injury involving both the extrahepatic portion of the left hepatic duct and its confluence with the right hepatic duct. This injury was successfully diagnosed and treated using ERCP.

CD18 deficiency improves liver injury in the MCD model of steatohepatitis.

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Pierce, Andrew A; Duwaerts, Caroline C; Siao, Kevin; Mattis, Aras N; Goodsell, Amanda; Baron, Jody L; Maher, Jacquelyn J

2017-01-01

Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.

A rare case of hepatic duct injury from blunt abdominal trauma.

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Hasaniya, Nahidh W; Premaratne, Shyamal; Premaratne, Ishani D; McNamara, J Judson

2013-01-01

A 25 year-old male was brought to the emergency room following an apparent suicide attempt by jumping from the fourth floor. Patient had a large abdominal laceration in the right upper quadrant (RUQ). CT scan showed a sub-scapular hematoma of the liver. Due to the repeated episodes of hypotension, a laporotomy was performed and the left hepatic artery was ligated while the ductal injury was managed with a Roux-en-Y left hepatic jejunostomy and stent. Bile leakage was resolved post-operatively by day 5 and the patient was discharged home on day 13 after clearance from psychiatry. While non-iatrogenic extrahepatic biliary trauma is rare, a high degree of suspicion is essential, especially in cases like the one discussed in this report. Diagnosis can be difficult in patients undergoing observation.

Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol

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Kaphalia, Bhupendra S.; Bhopale, Kamlesh K.; Kondraganti, Shakuntala; Wu Hai; Boor, Paul J.; Ansari, G.A. Shakeel

2010-01-01

Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH - ) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH - and hepatic ADH-normal (ADH + ) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2 months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ∼ 1.5-fold greater in ADH - vs. ADH + deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH - deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

Predictive factors for early failure of transarterial embolization in blunt hepatic injury patients

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Lee, Y.-H.; Wu, C.-H.; Wang, L.-J.; Wong, Y.-C.; Chen, H.-W.; Wang, C.-J.; Lin, B.-C.; Hsu, Y.-P.

2014-01-01

Aim: To evaluate the early success of transarterial embolization (TAE) in patients with traumatic liver haemorrhage and to determine independent factors for its failure. Materials and methods: From January 2009 to December 2012, TAE was performed in 48 patients for traumatic liver haemorrhage. Their medical charts were reviewed for demographic information, pre-TAE vital signs and laboratory data, injury grade, type of contrast medium extravasation (CME) at CT, angiography findings, and early failure. “Early failure” was defined as the need for repeated TAE or a laparotomy for hepatic haemorrhage within 4 days after TAE. Variables were compared between the early success and early failure groups. Variables with univariate significance were also analysed using multivariate logistic regression for predictors of early failure. Results: Among 48 liver TAE cases, nine (18.8%) were early failures due to liver haemorrhage. Early failure was associated with injury grade (p = 0.039), major liver injury (grades 4 and 5; p = 0.007), multiple CMEs at angiography (p = 0.031), incomplete TAE (p = 0.002), and elevated heart rate (p = 0.026). Incomplete embolization (OR = 8; p = 0.042), and heart rate >110 beats/min (bpm; OR = 8; p = 0.05) were independent factors for early failure of TAE in the group with major liver injuries. Conclusion: Major hepatic injury is an important factor in early failure. Patients with a heart rate >110 bpm and incomplete embolization in the major injury group have an increased rate of early failure. The success rate of proximal TAE was comparable to that of the more time-consuming, superselective, distal TAE. - Highlights: • Early failure of TAE is associated with a higher grade of liver injury. • Incomplete embolization is more likely to suffer early failure of TAE. • A heart rate greater than 110 bpm is more likely to suffer early failure of TAE. • We recommend proximal embolization to prevent early failure of TAE

Core promoter mutations 3 years after anti-hepatitis B e seroconversion in patients with chronic hepatitis B or hepatitis B and C infection and cancer remission.

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Zampino, Rosa; Marrone, Aldo; Karayiannis, Peter; Cirillo, Grazia; del Giudice, Emanuele Miraglia; Rania, Giovanni; Utili, Riccardo; Ruggiero, Giuseppe

2002-09-01

In this study, we aimed to evaluate the persistence of hepatitis B virus (HBV) DNA and the role of HBV core promoter and precore region mutations in 28 young cancer survivor patients with HBV or HBV and hepatitis C virus (HCV) infections, and persistently normal ALT levels, after spontaneous or interferon (IFN)-induced anti-hepatitis B e (HBe) seroconversion. Sera from 15 patients with HBV and 13 with dual HBV-HCV infection were analyzed for the presence of HBV-DNA and HCV-RNA by polymerase chain reaction 3 yr after anti-HBe seroconversion. A total of 21 patients had seroconverted spontaneously and seven did so after IFN treatment. The core promoter and the precore regions were amplified sequenced directly. Among patients with HBV infection, HBV-DNA was detected in five of nine (55%) with spontaneous anti-HBe and in all six treated patients (p = 0.092). In the coinfected patients, four had cleared both HBV-DNA and HCV-RNA, five were HBV-DNA negative/HCV-RNA positive and four had the reverse viral pattern. Among the 15 patients with persistence of HBV-DNA, a 7-base pair nucleotide deletion in the core promoter (1757-1763) was present in seven of 10 patients with spontaneous and in one of five patients with IFN-induced seroconversion (p = 0.033). The G1896A precore stop codon mutation was never observed. HBV-DNA levels were significantly lower in patients with the core promoter deletion (p = 0.011). The 7-base pair deletion generated a truncated X protein at amino-acid position 132. A core promoter deletion after anti-HBe seroconversion was associated with low HBV-DNA levels, probably because of downregulation of pregenomic RNA production and truncation of the X protein. HBV-DNA persistence was a frequent event, even in the absence of active liver disease.

The protective effect of huperzine A against hepatic ischemia reperfusion injury in mice.

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Yang, Y; Yang, J; Jiang, Q

2014-06-01

Nowadays, hepatic ischemia reperfusion (HI/R) injury is regarded as a serious concern in clinical practices. Huperzine A (HupA) is an alkaloid isolated from the Chinese folk medicine huperzia serrate, which has possessed diverse pharmacological actions. A mouse model of HI/R was caused by clamping the hepatic artery, the hepatoportal vein, and the bile duct with a vascular clamp for 30 minutes followed by reperfusion for 6 hours under anesthesia. The sham group experienced the identical procedure without hepatic ischemia. The HupA group received an injection into the tail vein 5 minutes prior to HI/R at the doses of 167 and 500 μg/kg. The vehicle group was injected with physiological saline instead of HupA. The liver function was assessed by determinations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA), and glutathione (GSH) were also measured spectrophotometrically. In addition, the activities of hepatic inflammatory mediators such as nuclear factor kappa B (NF-κB) p65, tumor necrosis factors-α (TNF-α, interleukin-1β (IL-1β) and IL-6 were also measured. Furthermore, the apoptotic damage was evaluated by measuring caspase-3 activity in hepatic tissues. Treatment with HupA in mice at the doses of 167 and 500 μg/kg remarkably reduced serum ALT and AST activities in HupA-treated ischemic mice. Furthermore, HupA treatment could enhance the activities of hepatic tissue SOD, CAT, and GSH but decrease MDA tissue content. The activities of inflammatory cytokines including NF-κB p65, TNF-α, IL-1β and IL-6 were all decreased in ischemic mice treated with HupA. Colorimetric test results illustrated that a marked reduction of caspase-3 activity was found in the HupA-treated group compared with the vehicle group. Our present data suggest that HupA has a protective role against HI/R injury of mice and antioxidative, anti-inflammatory, and antiapoptotic

Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.

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Shaker, Mohamed E; Zalata, Khaled R; Mehal, Wajahat Z; Shiha, Gamal E; Ibrahim, Tarek M

2011-04-15

Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(4)-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. Copyright © 2011 Elsevier Inc. All rights reserved.

Hepatitis B X-interacting protein promotes cisplatin resistance and regulates CD147 via Sp1 in ovarian cancer.

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Zou, Wei; Ma, Xiangdong; Yang, Hong; Hua, Wei; Chen, Biliang; Cai, Guoqing

2017-03-01

Ovarian cancer is the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure in malignant tumors. Hepatitis B X-interacting protein acts as an oncoprotein, regulates cell proliferation, and migration in breast cancer. We aimed to investigate the effects and mechanisms of hepatitis B X-interacting protein on resistance to cisplatin in human ovarian cancer cell lines. The mRNA and protein levels of hepatitis B X-interacting protein were detected using RT-PCR and Western blotting in cisplatin-resistant and cisplatin-sensitive tissues, cisplatin-resistant cell lines A2780/CP and SKOV3/CP, and cisplatin-sensitive cell lines A2780 and SKOV3. Cell viability and apoptosis were measured to evaluate cellular sensitivity to cisplatin in A2780/CP cells. Luciferase reporter gene assay was used to determine the relationship between hepatitis B X-interacting protein and CD147. The in vivo function of hepatitis B X-interacting protein on tumor burden was assessed in cisplatin-resistant xenograft models. The results showed that hepatitis B X-interacting protein was highly expressed in ovarian cancer of cisplatin-resistant tissues and cells. Notably, knockdown of hepatitis B X-interacting protein significantly reduced cell viability in A2780/CP compared with cisplatin treatment alone. Hepatitis B X-interacting protein and cisplatin cooperated to induce apoptosis and increase the expression of c-caspase 3 as well as the Bax/Bcl-2 ratio. We confirmed that hepatitis B X-interacting protein up-regulated CD147 at the protein expression and transcriptional levels. Moreover, we found that hepatitis B X-interacting protein was able to activate the CD147 promoter through Sp1. In vivo, depletion of hepatitis B X-interacting protein decreased the tumor volume and weight induced by cisplatin. Taken together, these results indicate that hepatitis B X-interacting protein promotes cisplatin resistance and regulated CD147 via Sp1 in

Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats

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Xufeng Tao

2016-07-01

Full Text Available The effects of total flavonoids (TFs from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST, alanine aminotransferase (ALT, myeloperoxidase (MPO, and lactate dehydrogenase (LDH activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA and increased the levels of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px, which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β, interleukin-1 (IL-6, and tumor necrosis factor alpha (TNF-α. Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease.

Effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury

Directory of Open Access Journals (Sweden)

Yin-Tian Deng

2016-11-01

Full Text Available Objective: To study the effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury. Methods: A total of 68 patients with primary liver cancer who underwent left liver resection in our hospital between May 2012 and August 2015 were selected for study and divided into group A (selective hepatic inflow occlusion of left liver and group B (Prignle hepatic inflow occlusion according to different intraoperative blood occlusion methods, serum was collected before and after operation to determine liver enzyme content, the removed liver tissue was collected to determine energy metabolism indexes, inflammation indexes and oxidative stress indexes. Results: 1 d, 3 d and 5 d after operation, GPT, GOT, GGT, LDH and ALP content in serum of both groups were significantly higher than those before operation, and GPT, GOT, GGT, LDH and ALP content in serum of group A 1 d, 3 d and 5 d after operation were significantly lower than those of group B; ATP, ADP, AMP, PI3K, AKT, GSK3β, T-AOC, PrxI and Trx content in liver tissue of group A were significantly higher than those of group B while PTEN, IL-12p40, MDA and MPO content were significantly lower than those of group B. Conclusions: Selective hepatic inflow occlusion during liver cancer resection can reduce the liver ischemia-reperfusion injury, improve the energy metabolism of liver cells and inhibit inflammation and oxidative stress in liver tissue.

Prevalence of hepatitis B virus subgenotypes and basal core promoter, precore variants in patients with acute hepatitis B in central Vietnam.

Science.gov (United States)

Hayashi, Kazuhiko; Katano, Yoshiaki; Chuong, Tran Xuan; Takeda, Yasushi; Ishigami, Masatoshi; Itoh, Akihiro; Hirooka, Yoshiki; Nakano, Isao; Huy, Tran Van; Minh, Nguyen Ngoc; Diem, Tran thi Minh; An, Dong thi Hoai; Phiet, Pham Hoang; Goto, Hidemi

2009-01-01

Hepatitis B virus (HBV) has been classified into 8 genotypes that have different geographic distributions. The clinical outcomes of acute hepatitis are dependent on genotype. The aim of this study was to investigate the distribution of HBV subgenotypes and basal core promoter (BCP)/precore (PC) regions in acute hepatitis patients in Central Vietnam to clarify the distributions and the clinical and virological differences. 27 patients with acute hepatitis B were studied. HBV subgenotypes and BCP/PC variants were determined by direct sequencing of the preS, BCP/PC regions, respectively. HBV subgenotypes B4/Ba (n = 22) and C1/Cs (n = 5) were detected. Of the 27 patients, 3 developed fulminant hepatic failure, and all were infected with B4/Ba. Three patients had a BCP mutation, and 10 patients had a PC mutation in subgenotype B4/Ba. Three patients with C1/Cs had a BCP mutation. Two of 3 patients who progressed to fulminant hepatic failure had T1762, A1764, and A1896 simultaneously. None of the patients with acute, self-limited hepatitis carried these triple mutations. The prevalent HBV subgenotypes in patients with acute hepatitis B in Central Vietnam were B4/Ba and C1/Cs. BCP/PC variants have an association with the development of fulminant hepatic failure in subgenotype B4/Ba. Copyright 2009 S. Karger AG, Basel.

Only Moderate Intra- and Inter-observer Agreement between Radiologists and Surgeons when Grading Blunt Paediatric Hepatic Injury on CT Scan

NARCIS (Netherlands)

Nellensteijn, D. R.; ten Duis, H. J.; Oldenziel, J.; Polak, W. G.; Hulscher, J. B. F.

2009-01-01

Introduction: The American Pediatric Surgical Association developed guidelines for the management of haemodynamically stable children with hepatic or splenic injury, based on grade of injury on CF scan. This study investigated the intra- and inter-observer agreement of radiologists, paediatric

5-lipoxygenase activation is involved in the mechanisms of chronic hepatic injury in a rat model of chronic aluminum overload exposure

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Mai, Shaoshan [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China); He, Qin [Department of Heptobiliary Surgery, 1st Affiliated Hospital, Chongqing Medical University, Chongqing 400016 (China); Wang, Hong; Hu, Xinyue; Luo, Ying; Yang, Yang; Kuang, Shengnan; Tian, Xiaoyan; Ma, Jie [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China); Yang, Junqing, E-mail: 1139627371@qq.com [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China)

2016-08-15

We previously confirmed that rats overloaded with aluminum exhibited hepatic function damage and increased susceptibility to hepatic inflammation. However, the mechanism of liver toxicity by chronic aluminum overload is poorly understood. In this study, we investigated changes in the 5-lipoxygenase (5-LO) signaling pathway and its effect on liver injury in aluminum-overloaded rats. A rat hepatic injury model of chronic aluminum injury was established via the intragastric administration of aluminum gluconate (Al{sup 3+} 200 mg/kg per day, 5 days a week for 20 weeks). The 5-LO inhibitor, caffeic acid (10 and 30 mg/kg), was intragastrically administered 1 h after aluminum administration. Hematoxylin and eosin staining was used to visualize pathological changes in rat liver tissue. A series of biochemical indicators were measured with biochemistry assay or ELISAs. Immunochemistry and RT-PCR methods were used to detect 5-LO protein and mRNA expression in the liver, respectively. Caffeic acid administration protected livers against histopathological injury, decreased plasma ALT, AST, and ALP levels, decreased TNF-α, IL-6, IL-1β and LTs levels, increased the reactive oxygen species content, and down-regulated the mRNA and protein expressions of 5-LO in aluminum overloaded rats. Our results indicate that 5-lipoxygenase activation is mechanistically involved in chronic hepatic injury in a rat model of chronic aluminum overload exposure and that the 5-LO signaling pathway, which associated with inflammation and oxidative stress, is a potential therapeutic target for chronic non-infection liver diseases. - Highlights: • 5-LO signaling contributes to mechanisms of hepatotoxicity of aluminum overload. • Oxidative and inflammatory reaction involve in chonic aluminum hepatotoxicity. • 5-LO inhibitor has a protective effect on aluminum-overload liver injury. • 5-LO signaling is a potential therapeutic target for non-infection liver diseases.

9Th Injury Prevention and Safety Promotion Conference, Melbourne ...

African Journals Online (AJOL)

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The 9th Injury Prevention and Safety Promotion Conference was held in Melbourne,. Australia, from 24 to 26 July 2009. This conference formed part of a series of conferences initiated in 1993 by the Monash University's Accident Research Centre (MOARC) in partnership ... outputs in injury presentation work. The speaker ...

Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens.

Science.gov (United States)

Yang, Weijian; Liu, Yong; Liu, Baolong; Tan, Huajun; Lu, Hao; Wang, Hong; Yan, Hua

2016-08-24

Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4(+)T/CD8(+)T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections.

[Morbimortality in patients with hepatic trauma].

Science.gov (United States)

Fonseca-Neto, Olival Cirilo Lucena da; Ehrhardt, Rogério; Miranda, Antonio Lopes de

2013-06-01

The liver is the intra-abdominal organ more injured in patient victims of trauma. The injury occurs more frequently in the penetrating trauma. The incidence of mortality for injuries of the liver is 10%. To evaluate the mortality of the patients with hepatic trauma, the treatment applied and its evolution. Were analyzed, retrospectively, the charts of all patients with hepatic trauma and surgical indication. Were analyzed: gender, age, ISS (injury severity score), classification of the abdominal trauma type (open or closed), causing instrument of the open traumas, degree of the injury, hepatic segments involved, presence of associated injuries, type of surgical treatment: not-therapeutic laparotomy and therapeutic laparotomy, reoperations, complications, time of hospitalization in days and mortality. One hundred and thirty-seven patients participated. Of these, 124 were men (90.5%). The majority (56.2%) had 20-29 years old. Closed abdominal trauma was most prevalent (67.9%). Of the penetrating traumas, the originated with firearms were in 24.8%. One hundred and three patients had only one injured hepatic segment (75.2%) and 34 (24.8%) two. Grade II injuries were in 66.4%. Of the 137 patients with laparotomy, 89 had been not-therapeutic, while in 48 it was necessary to repair associated injuries. Spleen and diaphragm had been the more frequently injured structures, 30% and 26%, respectively. The ISS varied of eight to 72, being the ISS > 50 (eight patients) associate with fatal evolution (five patients). Biliary fistula and hepatic abscess had been the main complications. Seven deaths had occurred. Concomitant injuries, hepatic and other organs, associated with ISS > 50 presented higher possibility of complications and death.

Hepatic injury after whole-liver irradiation in the rat

International Nuclear Information System (INIS)

Geraci, J.P.; Jackson, K.L.; Mariano, M.S.; Leitch, J.M.

1985-01-01

Radiation-induced hepatic injury in rats, which is characterized by marked ascites accompanied by liver necrosis, fibrosis, and vein lesions, is described in this study. These adverse sequelae are produced within 30 days after irradiation if there is surgical removal of two-thirds of the liver immediately after whole-liver irradiation. The LD/sub 50/30/ day and median survival time after liver irradiation and two-thirds partial hepatectomy is 24 Gy and 17 days, respectively. Death is preceded by reduction in liver function as measured by [ 131 I]-labeled rose bengal clearance. Prior to death, liver sepsis and endotoxemia were detected in most irradiated, partially hepatectomized animals. Pretreatment of the animals with endotoxin and/or antibiotic decontamination of the GI tract resulted in increased survival time, but no irradiated, partially hepatectomized animal survived beyond 63 days. This suggests that sepsis and endotoxemia resulting from the bacteria in the intestine are the immediate cause of death after 30-Gy liver irradiation and partial hepatectomy. It is concluded that the hepatectomized rat model is an economical and scientifically manageable experimental system to study a form of radiation hepatitis that occurs in compromised human livers

Hepatic drug clearance following traumatic injury.

Science.gov (United States)

Slaughter, R L; Hassett, J M

1985-11-01

Trauma is a complex disease state associated with physiologic changes that have the potential to alter hepatic drug clearance mechanisms. These responses include alterations in hepatic blood flow, reduction in hepatic microsomal activity, reduction in hepatic excretion processes, and changes in protein binding. Hepatic blood flow is influenced by sympathomimetic activity. Both animal and human studies demonstrate an initial reduction and subsequent increase in hepatic blood flow, which coincides with an observed increase and subsequent return to normal in serum catecholamine concentrations. Unfortunately, there are no human studies that address the importance these findings may have to the clearance processes of high intrinsic clearance compounds. Animal studies of trauma indicate that hepatic microsomal activity is depressed during the post-traumatic period. Reduction in the hepatic clearance of antipyrine, a model low intrinsic compound, has also been demonstrated in animal models of trauma. In addition to these effects, hepatic excretion of substances such as indocyanine green and bilirubin have been demonstrated to be impaired in both traumatized animals and humans. Finally, substantial increases in the serum concentration of the binding protein alpha 1-acid glycoprotein occur in trauma patients. This has been reported to be associated with subsequent decreases in the free fraction of lidocaine and quinidine. In addition to changing serum drug concentration/response relationships, the pharmacokinetic behavior of drugs bound to alpha 1-acid glycoprotein should also change. Preliminary observations in our laboratory in a dog model of surgically-induced trauma have shown a reduction in the total clearance of lidocaine and reduction in free lidocaine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoksisk hepatitis

DEFF Research Database (Denmark)

Amadid, Hanan; Schiødt, Frank Vinholt

2014-01-01

Hypoxic hepatitis (HH), also known as ischaemic hepatitis or shock liver, is an acute liver injury caused by hepatic hypoxia. Cardiac failure, respiratory failure and septic shock are the main underlying conditions. In each of these conditions, several haemodynamic mechanisms lead to hepatic...... hypoxia. A shock state is observed in only 50% of cases. Thus, shock liver and ischaemic hepatitis are misnomers. HH can be a diagnostic pitfall but the diagnosis can be established when three criteria are met. Prognosis is poor and prompt identification and treatment of the underlying conditions...

Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

Science.gov (United States)

Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

2016-06-01

We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent.

Science.gov (United States)

Tetri, Laura H; Basaranoglu, Metin; Brunt, Elizabeth M; Yerian, Lisa M; Neuschwander-Tetri, Brent A

2008-11-01

The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

International Nuclear Information System (INIS)

Shaker, Mohamed E.; Zalata, Khaled R.; Mehal, Wajahat Z.; Shiha, Gamal E.; Ibrahim, Tarek M.

2011-01-01

Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl 4 ) rat model. Male Wistar rats received intraperitoneal injections of CCl 4 twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl 4 -intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl 4 -induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl 4 -treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl 4 -induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. - Graphical abstract: Display Omitted Research Highlights: → The anti-fibrotic effects of imatinib, nilotinib and silymarin were compared. → These effects were

Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

Science.gov (United States)

Chen, Zong; Ding, Tao; Ma, Chuan-Gen

2017-11-18

Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD-containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-κB) through interacting with IKKα and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5 -/- ) mice. Our results indicated that NLRC5 -/- showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/R injury, WT and NLRC5 -/- mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5 -/- hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pre-treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Computed tomography in hepatic trauma

International Nuclear Information System (INIS)

Moon, K.L. Jr.; Federle, M.P.

1983-01-01

Twenty-five patients with hepatic injury from blunt upper abdominal trauma were examined by computed tomography (CT). The spectrum of CT findings was recorded, and the size of the hepatic laceration and the associated hemoperitoneum were correlated with the mode of therapy used in each case (operative vs nonoperative). While the need for surgery correlated roughly with the size of the hepatic laceration, the size of the associated hemoperitoneum was an important modifying factor. Fifteen patients with hepatic lacerations but little or no hemoperitoneum were managed nonoperatively. CT seems to have significant advantages over hepatic scintigraphy, angiography, and diagnostic peritoneal lavage. By combining inforamtion on the clinical state of the patient and CT findings, therapy of hepatic injury can be individualized and the incidence of nontherapeutic laparotomies decreased

Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

Science.gov (United States)

Khalifa, Hesham A.; Al-Quraishy, Saleh A.

2017-01-01

The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID:28819543

Effects of hepatic ischemia-reperfusion injury on the blood-brain barrier permeability to [14C] and [13C]sucrose.

Science.gov (United States)

Miah, Mohammad K; Bickel, Ulrich; Mehvar, Reza

2017-12-01

Hepatic encephalopathy that is associated with severe liver failure may compromise the blood-brain barrier (BBB) integrity. However, the effects of less severe liver diseases, in the absence of overt encephalopathy, on the BBB are not well understood. The goal of the current study was to investigate the effects of hepatic ischemia-reperfusion (IR) injury on the BBB tight junction permeability to small, hydrophilic molecules using the widely used [ 14 C]sucrose and recently-proposed alternative [ 13 C]sucrose as markers. Rats were subjected to 20 min of hepatic ischemia or sham surgery, followed by 8 h of reperfusion before administration of a single bolus dose of [ 14 C] or [ 13 C]sucrose and collection of serial (0-30 min) blood and plasma and terminal brain samples. The concentrations of [ 14 C] and [ 13 C]sucrose in the samples were determined by measurement of total radioactivity (nonspecific) and LC-MS/MS (specific), respectively. IR injury significantly increased the blood, plasma, and brain concentrations of both [ 14 C] and [ 13 C]sucrose. However, when the brain concentrations were corrected for their respective area under the blood concentration-time curve, only [ 14 C]sucrose showed significantly higher (30%) BBB permeability values in the IR animals. Because [ 13 C]sucrose is a more specific BBB permeability marker, these data indicate that our animal model of hepatic IR injury does not affect the BBB tight junction permeability to small, hydrophilic molecules. Methodological differences among studies of the effects of liver diseases on the BBB permeability may confound the conclusions of such studies.

Improving Survival and Promoting Respiratory Motor Function After Cervical Spinal Cord Injury

Science.gov (United States)

2017-09-01

AWARD NUMBER: W81XWH-15-1-0378 TITLE: Improving Survival and Promoting Respiratory Motor Function After Cervical Spinal Cord Injury PRINCIPAL...TITLE AND SUBTITLE CordCorInjury 5a. CONTRACT NUMBER Improvi g Survival and Promoting Respiratory Motor Function After Cervical Spinal Cord...care. However, despite these drastic interventions, the cervical injured patient is still susceptible to death due to respiratory complications

Biochemical metabolic changes assessed by 31P magnetic resonance spectroscopy after radiation-induced hepatic injury in rabbits

Science.gov (United States)

Yu, Ri-Sheng; Hao, Liang; Dong, Fei; Mao, Jian-Shan; Sun, Jian-Zhong; Chen, Ying; Lin, Min; Wang, Zhi-Kang; Ding, Wen-Hong

2009-01-01

AIM: To compare the features of biochemical metabolic changes detected by hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) with the liver damage score (LDS) and pathologic changes in rabbits and to investigate the diagnostic value of 31P MRS in acute hepatic radiation injury. METHODS: A total of 30 rabbits received different radiation doses (ranging 5-20 Gy) to establish acute hepatic injury models. Blood biochemical tests, 31P MRS and pathological examinations were carried out 24 h after irradiation. The degree of injury was evaluated according to LDS and pathology. Ten healthy rabbits served as controls. The MR examination was performed on a 1.5 T imager using a 1H/31P surface coil by the 2D chemical shift imaging technique. The relative quantities of phosphomonoesters (PME), phosphodiesters (PDE), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. The data were statistically analyzed. RESULTS: (1) Relative quantification of phosphorus metabolites: (a) ATP: there were significant differences (P < 0.05) (LDS-groups: control group vs mild group vs moderate group vs severe group, 1.83 ± 0.33 vs 1.55 ± 0.24 vs 1.27 ± 0.09 vs 0.98 ± 0.18; pathological groups: control group vs mild group vs moderate group vs severe group, 1.83 ± 0.33 vs 1.58 ± 0.25 vs 1.32 ± 0.07 vs 1.02 ± 0.18) of ATP relative quantification among control group, mild injured group, moderate injured group, and severe injured group according to both LDS grading and pathological grading, respectively, and it decreased progressively with the increased degree of injury (r = -0.723, P = 0.000). (b) PME and Pi; the relative quantification of PME and Pi decreased significantly in the severe injured group, and the difference between the control group and severe injured group was significant (P < 0.05) (PME: LDS-control group vs LDS-severe group, 0.86 ± 0.23 vs 0.58 ± 0.22, P = 0.031; pathological control group vs pathological severe group, 0.86 ± 0.23 vs 0.60 �

Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

Science.gov (United States)

Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

2017-04-01

For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (PBCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.

CT-based injury classification

International Nuclear Information System (INIS)

Mirvis, S.E.; Whitley, N.O.; Vainright, J.; Gens, D.

1988-01-01

Review of preoperative abdominal CT scans obtained in adults after blunt trauma during a 2.5-year period demonstrated isolated or predominant liver injury in 35 patients and splenic injury in 33 patients. CT-based injury scores, consisting of five levels of hepatic injury and four levels of splenic injury, were correlated with clinical outcome and surgical findings. Hepatic injury grades I-III, present in 33 of 35 patients, were associated with successful nonsurgical management in 27 (82%) or with findings at celiotomy not requiring surgical intervention in four (12%). Higher grades of splenic injury generally required early operative intervention, but eight (36%) of 22 patients with initial grade III or IV injury were managed without surgery, while four (36%) of 11 patients with grade I or II injury required delayed celiotomy and splenectomy (three patients) or emergent rehospitalization (one patient). CT-based injury classification is useful in guiding the nonoperative management of blunt hepatic injury in hemodynamically stable adults but appears to be less reliable in predicting the outcome of blunt splenic injury

Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

Directory of Open Access Journals (Sweden)

Kamran Qureshi

2014-01-01

Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.

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Toyoda, Tomomi; Tosaka, Shinya; Tosaka, Reiko; Maekawa, Takuji; Cho, Sungsam; Eguchi, Susumu; Nakashima, Masahiro; Sumikawa, Koji

2014-01-01

Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS). Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed. Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects. Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Cardiopulmonary bypass after severe blunt hepatic injury: management of multi-system blunt trauma in an adolescent.

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Streit, Stephanie; Kavarana, Minoo; Scheurer, Mark A; Cina, Robert A

2013-06-01

A 16-year-old adolescent male sustained combined injuries to the tricuspid valve and liver. This injury is exceptional due to the mechanism and the circumstances in which it took place: a flying pumpkin thrown from a sport utility vehicle. An echocardiogram demonstrated a flail chordal apparatus associated with the posterior leaflet of the tricuspid valve, creating substrate for severe tricuspid regurgitation with preserved right heart function. He was treated with non-operative management for the liver injury; he remained hemodynamically stable and was discharged home. He underwent successful repair of the tricuspid valve 17 days following the initial injury necessitating systemic anticoagulation and was discharged home two days later. The patient recovered fully without residual valvular pathology or hepatic sequelae. Copyright © 2013 Elsevier Inc. All rights reserved.

Multidisciplinary approach for the management of complex hepatic injuries AAST-OIS grades IV-V: a prospective study.

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Asensio, J A; Petrone, P; García-Núñez, L; Kimbrell, B; Kuncir, E

2007-01-01

Complex hepatic injuries grades IV-V are highly lethal. The objective of this study is to assess the multidisciplinary approach for their management and to evaluate if survival could be improved with this approach. Prospective 54-month study of all patients sustaining hepatic injuries grades IV-V managed operatively at a Level I Trauma Center. survival. univariate and stepwise logistic regression. Seventy-five patients sustained penetrating (47/63%) and blunt (28/37%) injuries. Seven (9%) patients underwent emergency department thoracotomy with a mortality of 100%. Out of the 75 patients, 52 (69%) sustained grade IV, and 23 (31%) grade V. The estimated blood loss was 3,539+/-3,040 ml. The overall survival was 69%, adjusted survival excluding patients requiring emergency department thoracotomy was 76%. Survival stratified to injury grade: grade IV 42/52-81%, grade V 10/23-43%. Mortality grade IV versus V injuries (p < 0.002; RR 2.94; 95% CI 1.52-5.70). Risk factors for mortality: packed red blood cells transfused in operating room (p=0.024), estimated blood loss (p < 0.001), dysryhthmia (p < 0.0001), acidosis (p = 0.051), hypothermia (p = 0.04). The benefit of angiography and angioembolization indicated: 12% mortality (2/17) among those that received it versus a 36% mortality (21/58) among those that did not (p = 0.074; RR 0.32; 95% CI 0.08-1.25). Stepwise logistic regression identified as significant independent predictors of outcome: estimated blood loss (p= 0.0017; RR 1.24; 95% CI 1.08-1.41) and number of packed red blood cells transfused in the operating room (p = 0.0358; RR 1.16; 95% CI 1.01-1.34). The multidisciplinary approach to the management of these severe grades of injuries appears to improve survival in these highly lethal injuries. A prospective multi-institutional study is needed to validate this approach.

[Surgical management, prognostic factors, and outcome in hepatic trauma].

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Ott, R; Schön, M R; Seidel, S; Schuster, E; Josten, C; Hauss, J

2005-02-01

Hepatic trauma is a rare surgical emergency with significant morbidity and mortality. Extensive experience in liver surgery is a prerequisite for the management of these injuries. The medical records of 68 consecutive patients with hepatic trauma were retrospectively reviewed for the severity of liver injury, management, morbidity, mortality, and risk factors. Of the patients, 14 were treated conservatively and 52 surgically (24 suture/fibrin glue, 16 perihepatic packing, 11 resections, 1 liver transplantation). Two patients died just before emergency surgery could be performed. Overall mortality was 21% (14/68), and 13, 14, 6, 27, and 50% for types I, II, III, IV, and V injuries, respectively. Only nine deaths (all type IV and V) were liver related, while four were caused by extrahepatic injuries and one by concomitant liver cirrhosis. With respect to treatment, conservative management, suture, and resection had a low mortality of 0, 4, and 9%, respectively. In contrast, mortality was 47% in patients in whom only packing was performed (in severe injuries). Stepwise multivariate regression analysis proved prothrombin values 30, and transfusion requirements of more than 10 red packed cells to be significant risk factors for post-traumatic death. Type I-III hepatic injuries can safely be treated by conservative or simple surgical means. However, complex hepatic injuries (types IV and V) carry a significant mortality and may require hepatic surgery, including liver resection or even transplantation. Therefore, patients with severe hepatic injuries should be treated in a specialized institution.

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction.

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Cruz-Antonio, L; Arauz, J; Franco-Bourland, R E; Guízar-Sahagún, G; Castañeda-Hernández, G

2012-08-01

Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). To determine the effect of acute SCI on the pharmacokinetics of diclofenac, a marker drug of intermediate hepatic extraction, administered by the intravenous and the oral routes. Female Wistar rats were submitted to complete section of the spinal cord at the T8 level. SCI and sham-injured rats received 3.2 mg kg(-1) of diclofenac sodium either intravenously or orally, diclofenac concentration was measured in whole blood samples and pharmacokinetic parameters were estimated. Diclofenac was not selected as test drug because of its therapeutic properties, but because to its biopharmaceutical properties, that is, intermediate hepatic extraction. Diclofenac bioavailability after intravenous administration was increased in injured rats compared with controls due to a reduced clearance. In contrast, oral diclofenac bioavailability was diminished in SCI animals due to a reduction in drug absorption, which overrides the effect on clearance. Acute SCI induces significant pharmacokinetic changes for diclofenac, a marker drug with intermediate hepatic extraction. SCI-induced pharmacokinetic changes are not only determined by injury characteristics, but also by the route of administration and the biopharmaceutical properties of the studied drug.

GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

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Hui Zhang

2014-01-01

Full Text Available Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK- 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP, and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB but enhanced the transcriptional activity of cAMP response element binding protein (CREB in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study.

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Patel, Kalyani R; Bertuch, Alison; Sasa, Ghadir S; Himes, Ryan W; Wu, Hao

2017-01-01

Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied. Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame. All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti-liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy). Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury.

Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice

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Swelm, Rachel P.L. van [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Laarakkers, Coby M.M. [Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Pertijs, Jeanne C.L.M.; Verweij, Vivienne; Masereeuw, Rosalinde [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Russel, Frans G.M., E-mail: F.Russel@pharmtox.umcn.nl [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands)

2013-06-01

Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75 mg/kg bw DF by oral gavage and 24 h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p < 0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p < 0.001 and p < 0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p < 0.001) and protein expression of PCNA (p < 0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24 h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury. - Highlights: • The urinary proteome shows biological processes involved in adverse drug reactions. • Urine proteins of DF-treated mice relate to kidney injury rather than liver injury. • Liver regeneration, not liver injury, is apparent 24h after oral DF administration. • Pretreatment with LPS does not enhance DF-induced liver injury in mice.

Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

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Kim, Young C.; Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

2007-01-01

Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards

Magnetic hydroxyapatite nanoworms for magnetic resonance diagnosis of acute hepatic injury

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Xu, Yun-Jun; Dong, Liang; Lu, Yang; Zhang, Le-Cheng; An, Duo; Gao, Huai-Ling; Yang, Dong-Mei; Hu, Wen; Sui, Cong; Xu, Wei-Ping; Yu, Shu-Hong

2016-01-01

Inorganic non-metallic biomaterials, including the silicon frustule of a unicellular diatom, the carbonate shell of a mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of an organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, is widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites have attracted great attention. Herein, we report a novel synthesis method of magnetic functionalized hydroxyapatite nanocomposites. By simply tuning the ratios of reactants, a series of hydroxyapatite-Fe3O4 worm-shaped nanocomposites (HAP-ION nanoworms) are obtained. In addition, layer-by-layer surface modifications with chitosan (CH) and sodium alginate (SA) were employed to improve the solubility and biocompatibility, and low cytotoxicity and no hemolysis were observed. With the increase of iron oxide nanocrystals, the magnetic properties of the magnetic assembled nanoworms were enhanced, which resulted in better performance of magnetic resonance (MR) imaging. Owing to the intravenous injection of HAP-ION nanoworms, the contrast to noise ratio (CNR) of hepatic MR imaging in vivo was enhanced obviously, which should be beneficial for hepatic injury grading and further therapeutic treatment.Inorganic non-metallic biomaterials, including the silicon frustule of a unicellular diatom, the carbonate shell of a mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of an organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, is widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites have attracted great attention. Herein, we report a novel synthesis method of magnetic

Growth Arrest-Specific Protein 6 is Hepatoprotective Against Ischemia/Reperfusion Injury

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Llacuna, Laura; Bárcena, Cristina; Bellido-Martín, Lola; Fernández, Laura; Stefanovic, Milica; Marí, Montserrat; García-Ruiz, Carmen; Fernández-Checa, José C.; de Frutos, Pablo García; Morales, Albert

2010-01-01

Growth arrest-specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here, we report an early increase in serum GAS6 levels following I/R exposure. Moreover, unlike wild type mice, Gas6-/- mice were highly sensitive to partial hepatic I/R, with 90% of mice dying within 12 hours of reperfusion due to massive hepatocellular injury. I/R induced early hepatic AKT phosphorylation in wild type but not in Gas6-/- mice, without significant changes in JNK phosphorylation or nuclear NF-κB translocation, whereas hepatic IL-1β and TNF mRNA levels were higher in Gas6-/- mice compared to wild type mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes protecting them from hypoxia-induced cell death, while GAS6 diminished lipopolysaccharide (LPS)-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, in vivo recombinant GAS6 treatment not only rescued GAS6 knockout mice from I/R-induced severe liver damage, but also attenuated hepatic damage in wild type mice following I/R. In conclusion, our data uncover GAS6 as a new player in liver I/R injury, emerging as a potential therapeutic target to reduce post-ischemic hepatic damage. PMID:20730776

Carbon Monoxide Protects against Hepatic Ischemia/Reperfusion Injury via ROS-Dependent Akt Signaling and Inhibition of Glycogen Synthase Kinase 3β

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Hyo Jeong Kim

2013-01-01

Full Text Available Carbon monoxide (CO may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3 and phosphatidylinositol 3-kinase (PI3K-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.

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Kim, Hyo Jeong; Joe, Yeonsoo; Kong, Jin Sun; Jeong, Sun-Oh; Cho, Gyeong Jae; Ryter, Stefan W; Chung, Hun Taeg

2013-01-01

Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

Effects of Urtica dioica on hepatic ischemia‐reperfusion injury in rats

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Kandis, Hayati; Karapolat, Sami; Yildirim, Umran; Saritas, Ayhan; Gezer, Suat; Memisogullari, Ramazan

2010-01-01

OBJECTIVES: To evaluate the effects of Urtica dioica on hepatic ischemia‐reperfusion injury. METHODS: Thirty adult male Wistar albino rats were divided into three groups: sham group (group 1), control group (group 2), and Urtica dioica group (group 3). All the rats were exposed to hepatic ischemia for 60 min, followed by 60 min of reperfusion. In group 2, a total of 2 ml/kg 0.9% saline solution was given intraperitoneally. In group 3, a total of 2 ml/kg Urtica dioica was given intraperitoneally. At the end of the procedure, liver tissue and blood samples were taken from all rats. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ceruloplasmin, catalase, paraoxonase, arylesterase, and lipid hydroperoxide levels were measured. Liver tissue histopathologies were also evaluated by light microscopy. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were significantly higher in group 2 than in group 1, and significantly lower in group 3 than in group 2. Also, group 2 had higher serum lipid hydroperoxides and ceruloplasmin levels but lower catalase, paraoxonase, and arylesterase levels than group 1. In group 3, serum lipid hydroperoxides and ceruloplasmin levels were significantly lower, and catalase, paraoxonase, and arylesterase levels were higher than those in group 2. Histopathological examination showed that liver tissue damage was significantly decreased in group 3 compared with group 2. CONCLUSIONS: Urtica dioica has a protective effect on the liver in hepatic ischemia‐reperfusion‐injured rats. PMID:21340227

Effects of Urtica dioica on hepatic ischemia-reperfusion injury in rats.

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Kandis, Hayati; Karapolat, Sami; Yildirim, Umran; Saritas, Ayhan; Gezer, Suat; Memisogullari, Ramazan

2010-01-01

To evaluate the effects of Urtica dioica on hepatic ischemia-reperfusion injury. Thirty adult male Wistar albino rats were divided into three groups: sham group (group 1), control group (group 2), and Urtica dioica group (group 3). All the rats were exposed to hepatic ischemia for 60 min, followed by 60 min of reperfusion. In group 2, a total of 2 ml/kg 0.9% saline solution was given intraperitoneally. In group 3, a total of 2 ml/kg Urtica dioica was given intraperitoneally. At the end of the procedure, liver tissue and blood samples were taken from all rats. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ceruloplasmin, catalase, paraoxonase, arylesterase, and lipid hydroperoxide levels were measured. Liver tissue histopathologies were also evaluated by light microscopy. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were significantly higher in group 2 than in group 1, and significantly lower in group 3 than in group 2. Also, group 2 had higher serum lipid hydroperoxides and ceruloplasmin levels but lower catalase, paraoxonase, and arylesterase levels than group 1. In group 3, serum lipid hydroperoxides and ceruloplasmin levels were significantly lower, and catalase, paraoxonase, and arylesterase levels were higher than those in group 2. Histopathological examination showed that liver tissue damage was significantly decreased in group 3 compared with group 2. Urtica dioica has a protective effect on the liver in hepatic ischemia-reperfusion-injured rats.

Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis.

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Giovanni Sitia

2011-06-01

Full Text Available Kupffer cells (KCs are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1 protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.

Hepatic arterial embolization in the management of blunt hepatic trauma: indications and complications.

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Letoublon, Christian; Morra, Irene; Chen, Yao; Monnin, Valerie; Voirin, David; Arvieux, Catherine

2011-05-01

The objective was to clarify the role of hepatic arterial embolization (AE) in the management of blunt hepatic trauma. Retrospective observational study of 183 patients with blunt hepatic trauma admitted to a trauma referral center over a 9-year period. The charts of 29 patients (16%) who underwent hepatic angiography were reviewed for demographics, injury specific data, management strategy, angiographic indication, efficacy and complications of embolization, and outcome. AE was performed in 23 (79%) of the patients requiring angiography. Thirteen patients managed conservatively underwent emergency embolization after preliminary computed tomography scan. Six had postoperative embolization after damage control laparotomy and four had delayed embolization. Arterial bleeding was controlled in all the cases. Sixteen patients (70%) had one or more liver-related complications; temporary biliary leak (n=11), intra-abdominal hypertension (n=14), inflammatory peritonitis (n=3), hepatic necrosis (n=3), gallbladder infarction (n=2), and compressive subcapsular hematoma (n=1). Unrecognized hepatic necrosis could have contributed to the late posttraumatic death of one patient. AE is a key element in modern management of high-grade liver injuries. Two principal indications exist in the acute postinjury phase: primary hemostatic control in hemodynamically stable or stabilized patients with radiologic computed tomography evidence of active arterial bleeding and adjunctive hemostatic control in patients with uncontrolled suspected arterial bleeding despite emergency laparotomy. Successful management of injuries of grade III upward often entails a combined angiographic and surgical approach. Awareness of the ischemic complications due to angioembolization is important.

Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice.

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Li, Jibiao; Woolbright, Benjamin L; Zhao, Wen; Wang, Yifeng; Matye, David; Hagenbuch, Bruno; Jaeschke, Hartmut; Li, Tiangang

2018-01-01

Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Impact of Liver Graft Injury on Cancer Recurrence Posttransplantation.

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Li, Chang-Xian; Man, Kwan; Lo, Chung-Mau

2017-11-01

Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.

Development and Validation of an Online Program for Promoting Self-Management among Korean Patients with Chronic Hepatitis B

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Jinhyang Yang

2013-01-01

Full Text Available The hepatitis B virus is second only to tobacco as a known human carcinogen. However, chronic hepatitis B usually does not produce symptoms and people feel healthy even in the early stages of live cancer. Therefore, chronically infected people should perceive it as a serious health problem and move on to appropriate health behaviour. The purpose of this paper is to develop and validate an online program for promoting self-management among Korean patients with chronic hepatitis B. The online program was developed using a prototyping approach and system developing life cycle method, evaluated by users for their satisfaction with the website and experts for the quality of the site. To evaluate the application of the online program, knowledge and self-management compliance of the subjects were measured and compared before and after the application of the online program. There were statistically significant increases in knowledge and self-management compliance in the user group. An online program with high accessibility and applicability including information, motivation, and behavior skill factors can promote self-management of the patient with chronic hepatitis B. Findings from this study allow Korean patients with chronic hepatitis B to engage in proactive and effective health management in the community or clinical practice.

Research on Protective Effect and Mechanism of Idazoxan on lps Attacked Acute Hepatic Injury

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Zhu, Junyu; Ying, Shangqi; Kang, Wenyuan; Huang, Wenjuan; Liang, Huaping

2018-01-01

Objective: To observe the protection effect of Idazoxan (IDA) on LPS induced acute hepatic injury, and to explore its action mechanism. Methods: 60 adult C57BL/6 mice were divided into a control group (20 mice, intraperitoneal injection of phosphate buffer), a model group (20 mice, intraperitoneal injection of LPS 10 mg/kg) and a agmatine group (20 mice, intraperitoneal injection of LPS 10 mg/kg and agmatine 200 mg/kg) according to random number table method. Blood and liver tissue were collected for preparation of tissue homogenate. Enzyme-linked immunosorbent assay (ELISA) was adopted for detecting tumor necrosis factor-α (TNF-α) and interleukin (IL- 1β and IL - 6) contents in the serum and liver tissue at 24h after molding. Automatic biochemical analyzer is used for determining alanine transaminase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level at 24h after molding; The liver tissue pathology changes were observed at 24h after molding. Macrophage RAW264.7 cells were stimulated by 10 μg/mL LPS and with or without IDA (100 μmol/L). 2’, 7’-dichlorofluoresce in diacetate (DCFH-DA) was used as a fluorescent probe for detection of intracellular reactive oxygen species (ROS) level; qRT - PCR method was used for detecting antioxidant enzymes HO-1 and NQO-1 mRNA expression level at 2h, 4h and 8 h. Results: mice in the model group suffered from depression, curling and food water forbidding at 6h after molding. Mice in the Idazoxan group have obviously better spirit and activity than that of model group. The serum ALT, AST and LDH level of LPS attacked acute hepatic injury mice can be effectively alleviated after Idazoxan treatment. The expression of proinflammatory factor TNF-α and IL-6 in the liver can be reduced. The liver showed obvious pathological changes at 24 h after injection, such as liver cell swelling, necrosis, congestion, inflammatory cell infiltration, etc.; The liver cell injury was prominently alleviated in IDA

EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice.

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Yona Goldshmit

Full Text Available Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.

African Safety Promotion: A Journal of Injury and Violence ...

African Journals Online (AJOL)

African Safety Promotion: A Journal of Injury and Violence Prevention. ... a tear, not a laceration”: Form J88 as evidence in prosecution of violence against women ... A quantitative exploration of the effects of workplace bullying on South African ...

Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression.

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Fu-Chao Liu

Full Text Available Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1 pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 min, followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight, or a single dose of tropisetron (1 mg/kg body weight with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight. Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST and alanine aminotransferases (ALT, hepatic myeloperoxidase (MPO activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3, intercellular adhesion molecule-1 (ICAM-1, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and macrophage inflammatory protein-1α (MIP-1α. These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic

Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression.

Science.gov (United States)

Liu, Fu-Chao; Yu, Huang-Ping; Hwang, Tsong-Long; Tsai, Yung-Fong

2012-01-01

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury

Ethanol negatively regulates hepatic differentiation of hESC by inhibition of the MAPK/ERK signaling pathway in vitro.

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Wei Gao

Full Text Available Alcohol insult triggers complex events in the liver, promoting fibrogenic/inflammatory signals and in more advanced cases, aberrant matrix deposition. It is well accepted that the regenerative capacity of the adult liver is impaired during alcohol injury. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; however, the effects of alcohol on stem cell differentiation in the liver are not well understood.We employed hepatic progenitor cells derived from hESCs to study the impact of ethanol on hepatocyte differentiation by exposure of these progenitor cells to ethanol during hepatocyte differentiation.We found that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitor cells in a dose-dependent manner. There was also a moderate cell cycle arrest at G1/S checkpoint in the ethanol treated cells, which is associated with a reduced level of cyclin D1 in these cells. Ethanol treatment specifically inhibited the activation of the ERK but not JNK nor the p38 MAP signaling pathway. At the same time, the WNT signaling pathway was also reduced in the cells exposed to ethanol. Upon evaluating the effects of the inhibitors of these two signaling pathways, we determined that the Erk inhibitor replicated the effects of ethanol on the hepatocyte differentiation and attenuated the WNT/β-catenin signaling, however, inhibitors of WNT only partially replicated the effects of ethanol on the hepatocyte differentiation.Our results demonstrated that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitors through inhibiting the MAPK/ERK signaling pathway, and subsequently attenuating the WNT signaling pathway. Thus, our finding provides a novel insight into the mechanism by which alcohol regulates cell fate selection of hESC-derived hepatic progenitor cells, and the identified pathways may provide therapeutic targets

Protective Effect of Urtica dioica on Liver Injury Induced By Hepatic Ischemia Reperfusion Injury in Rats

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Alpaslan TERZİ

2010-05-01

Full Text Available Background: This study was designed to investigate the effects of Urtica dioica on liverischemia reperfusion injury in rats. Methods: Thirty male Wistar-albino rats were used in this experimental study. Animals weredivided into three groups as sham operated (group 1, control (group 2, and Urtica dioicatreatment group (group 3. Urtica dioica 2ml/kg were administered intraperitoneally beforeischemia and immediately after the reperfusion. The levels of total antioxidant capacity, totalfree sulfidril group, Total oxidant status, Oxidative stress index, and myeloperoxidase in livertissues were measured. The serum levels of ALT, AST and LDH were also measuredResults: Total antioxidant capacity and total free sulfidril group in liver tissue were significantlyhigher in group 3 than in group 2. Oxidative stress index and myeloperoxidase in liver tissuewere significantly lower in group 3 than the group 2. The levels of liver enzymes in treatmentgroup were significantly lower than those in the control group. Histological tissue damage wasmilder in the treatment group than that in the control group.Conclusion: It is concluded that Urtica dioica increase the antioxidant capacity and decreaseoxidative stress and liver enzymes in the hepatic ischemi reperfusion injury of rats.

Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

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Zhou, Rui-Jun; Ye, Hua; Wang, Feng; Wang, Jun-Long; Xie, Mei-Lin

2017-11-04

Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions

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Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

2016-01-01

Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal bu...

Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats.

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Duman, Deniz Güney; Kumral, Zarife Nigâr Özdemir; Ercan, Feriha; Deniz, Mustafa; Can, Güray; Cağlayan Yeğen, Berrak

2013-08-28

Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

Influence of Kupffer cell inactivation on cycloheximide-induced hepatic injury

International Nuclear Information System (INIS)

Kumagai, Kazuyoshi; Kiyosawa, Naoki; Ito, Kazumi; Yamoto, Takashi; Teranishi, Munehiro; Nakayama, Hiroyuki; Manabe, Sunao

2007-01-01

In our previous study, we found that cycloheximide (CHX) induces hepatocellular necrosis as well as hepatocellular apoptosis. This article evaluates the role of Kupffer cells on cycloheximide-induced hepatic injury using gadolinium chloride (GdCl 3 ) for the inhibition of Kupffer cells. One group of rats was treated with CHX (CHX group), and another was treated with GdCl 3 before being treated with the same dose of CHX (GdCl 3 /CHX group). The necrotic change in the GdCl 3 /CHX group was exacerbated under the induction of hepatocellular apoptosis by the CHX treatment. A substantial diminution of the number of ED1- or ED2-positive cells was demonstrated in the GdCl 3 /CHX group compared to the CHX group. In addition, the degree of decrease in ED2-positive cells was more apparent than that in ED1-positive cells. Increases in the mRNA levels of IL-10 and Stat3 were observed in the CHX group, but not in the GdCl 3 /CHX group. On the other hand, the hepatic mRNA levels of chemokines and adhesion molecules such as Ccl20, LOX-1, and E-selectin were significantly increased only in the GdCl 3 /CHX group. Thus, Kupffer cell inactivation by the GdCl 3 treatment leads to a loss of the capacity to produce IL-10, supposedly resulting in the enhancement of pro-inflammatory cytokine activities such as tumor necrosis factor (TNF) signaling. These events are suggested to be a factor of the inflammatory exacerbation in the livers of the GdCl 3 /CHX group. In conclusion, Kupffer cells may play a role in protecting hepatic necroinflammatory changes by releasing anti-inflammatory cytokines following the hepatocellular apoptosis resulting from CHX treatment

Association Between MC-2 Peptide and Hepatic Perfusion and Liver Injury Following Resuscitated Hemorrhagic Shock.

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Matheson, Paul J; Fernandez-Botran, Rafael; Smith, Jason W; Matheson, Samuel A; Downard, Cynthia D; McClain, Craig J; Garrison, Richard N

2016-03-01

Hemorrhagic shock (HS) due to trauma remains a major cause of morbidity and mortality in the United States, despite continuing progression of advanced life support and treatment. Trauma is the third most common cause of death worldwide and is the leading cause of death in the 1- to 44-year-old age group. Hemorrhagic shock often progresses to multiple organ failure despite conventional resuscitation (CR) that restores central hemodynamics. To examine whether MC-2 would bind glycosaminoglycans to decrease proinflammatory cytokines' influence in the liver, minimize organ edema, prevent liver injury, and improve hepatic perfusion. MC-2, a synthetic octapeptide derived from the heparin-binding domain of murine interferon gamma (IFN-γ), binds glycosaminoglycans to modulate serum and interstitial cytokine levels and activity. A controlled laboratory study of 3y male Sprague-Dawley rats that were randomized to 4 groups of 8 each: sham, sham+MC-2 (50 mg/kg), HS/CR, or HS/CR+MC-2 (HS = 40% of baseline mean arterial pressure for 60 minutes; CR = return of shed blood and 2 volumes of saline). The study began in March, 2013. Effective hepatic blood flow (EHBF) by galactose clearance, wet-dry weights, cytokines, histopathology, complete metabolic panel, and complete blood cell count were performed at 4 hours after CR. MC-2 partially reversed the HS/CR-induced hepatic hypoperfusion at 3 and 4 hours postresuscitation compared with HS/CR alone. Effective hepatic blood flow decreased during the HS period from a mean (SD) of 7.4 (0.3) mL/min/100 g and 7.5 (0.5) mL/min/100g at baseline to 3.7 (0.4) mL/min/100g and 5.9 (0.5) mL/min/100g for the HS/CR and HS/CR+MC-2 groups, respectively (P hepatic blood flow remained constant in the sham groups throughout the experimental protocol. Organ edema was increased in the ileum and liver in the HS/CR vs sham group, and MC-2 decreased edema in the ileum vs the HS/CR group. MC-2 in HS also decreased levels of alanine aminotransferase

Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.

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Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao

2016-04-14

The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.

Aberrant GSTP1 promoter methylation predicts short-term prognosis in acute-on-chronic hepatitis B liver failure.

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Gao, S; Sun, F-K; Fan, Y-C; Shi, C-H; Zhang, Z-H; Wang, L-Y; Wang, K

2015-08-01

Glutathione-S-transferase P1 (GSTP1) methylation has been demonstrated to be associated with oxidative stress induced liver damage in acute-on-chronic hepatitis B liver failure (ACHBLF). To evaluate the methylation level of GSTP1 promoter in acute-on-chronic hepatitis B liver failure and determine its predictive value for prognosis. One hundred and five patients with acute-on-chronic hepatitis B liver failure, 86 with chronic hepatitis B (CHB) and 30 healthy controls (HC) were retrospectively enrolled. GSTP1 methylation level in peripheral mononuclear cells (PBMC) was detected by MethyLight. Clinical and laboratory parameters were obtained. GSTP1 methylation levels were significantly higher in patients with acute-on-chronic hepatitis B liver failure (median 16.84%, interquartile range 1.83-59.05%) than those with CHB (median 1.25%, interquartile range 0.48-2.47%; P chronic hepatitis B liver failure group, nonsurvivors showed significantly higher GSTP1 methylation levels (P chronic hepatitis B liver failure, GSTP1 methylation showed significantly better predictive value than MELD score [area under the receiver operating characteristic curve (AUC) 0.89 vs. 0.72, P chronic hepatitis B liver failure and shows high predictive value for short-term mortality. It might serve as a potential prognostic marker for acute-on-chronic hepatitis B liver failure. © 2015 John Wiley & Sons Ltd.

Ultrasound appearance of radiation-induced hepatic injury. Correlation with computed tomography and magnetic resonance imaging

International Nuclear Information System (INIS)

Garra, B.S.; Shawker, T.H.; Chang, R.; Kaplan, K.; White, R.D.

1988-01-01

The ultrasound findings in three cases of radiation-induced hepatic injury are described and compared with computed tomography and magnetic resonance imaging findings. Fatty infiltration of the liver was present in two of the cases in which concurrent chemotherapy was being administered. On ultrasound B-scans, the regions of radiation injury were hypoechoic relative to the remainder of the liver. This finding was more obvious in the patients with fatty livers. CT scans on the patients with fatty infiltrated livers showed higher attenuation in the irradiated region than in unexposed liver. In the patient where no fatty infiltration was present, the radiated section of liver had lower attenuation consistent with previous reports. Magnetic resonance imaging showed decreased signal in the exposed areas on T1 weighted images

Injury-activated glial cells promote wound healing of the adult skin in mice.

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Parfejevs, Vadims; Debbache, Julien; Shakhova, Olga; Schaefer, Simon M; Glausch, Mareen; Wegner, Michael; Suter, Ueli; Riekstina, Una; Werner, Sabine; Sommer, Lukas

2018-01-16

Cutaneous wound healing is a complex process that aims to re-establish the original structure of the skin and its functions. Among other disorders, peripheral neuropathies are known to severely impair wound healing capabilities of the skin, revealing the importance of skin innervation for proper repair. Here, we report that peripheral glia are crucially involved in this process. Using a mouse model of wound healing, combined with in vivo fate mapping, we show that injury activates peripheral glia by promoting de-differentiation, cell-cycle re-entry and dissemination of the cells into the wound bed. Moreover, injury-activated glia upregulate the expression of many secreted factors previously associated with wound healing and promote myofibroblast differentiation by paracrine modulation of TGF-β signalling. Accordingly, depletion of these cells impairs epithelial proliferation and wound closure through contraction, while their expansion promotes myofibroblast formation. Thus, injury-activated glia and/or their secretome might have therapeutic potential in human wound healing disorders.

Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.

Science.gov (United States)

Llacuna, Laura; Bárcena, Cristina; Bellido-Martín, Lola; Fernández, Laura; Stefanovic, Milica; Marí, Montserrat; García-Ruiz, Carmen; Fernández-Checa, José C; García de Frutos, Pablo; Morales, Albert

2010-10-01

Growth arrest-specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas6(-/-) mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6(-/-) mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1β (IL-1β) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6(-/-) mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished lipopolysaccharide-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage.

Thromboxane A{sub 2} receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment

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Minamino, Tsutomu [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ito, Yoshiya [Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ohkubo, Hirotoki [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Hosono, Kanako; Suzuki, Tatsunori [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Sato, Takehito [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ae, Takako; Shibuya, Akitaka [Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Sakagami, Hiroyuki [Departments of Anatomy, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Narumiya, Shuh [Department of Pharmacology, Kyoto University School of Medicine, Kyoto, 606-8315 (Japan); Koizumi, Wasaburo [Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Majima, Masataka, E-mail: mmajima@med.kitasato-u.ac.jp [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)

2012-02-15

It is thought that thromboxane A{sub 2} (TxA{sub 2}) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA{sub 2} is involved in liver repair. The objective of the present study was to examine the role of TxA{sub 2} receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl{sub 4}) was used to induce liver injury in TP knockout (TP{sup −/−}) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48 h, respectively, and then declined. In TP{sup −/−} mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP{sup −/−} mice, the accumulation of hepatic CD11b{sup +}/F4/80{sup +} macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C―C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl{sub 4}-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression. -- Highlights: ► TP enhances liver regeneration by CCl{sub 4}. ► TP accumulates macrophages. ► TP up-regulates MCP-1.

Functional role of monocytes and macrophages for the inflammatory response in acute liver injury

Directory of Open Access Journals (Sweden)

Henning W Zimmermann

2012-10-01

Full Text Available Different etiologies such as drug toxicity, acute viral hepatitis B or acetaminophen poisoning can cause acute liver injury (ALI or even acute liver failure (ALF. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF, interleukin-6 (IL-6, IL-1-beta or monocyte chemoattractant protein 1 (MCP-1, CCL2 as well as activating other non-parenchymal liver cells, e.g. endothelial or hepatic stellate cells (HSC. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g. via caspase activation, but also activate protective signaling pathways, e.g. via nuclear factor kappa B (NF-kB. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+ monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1 are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.

Hepatic Enzyme Decline after Pediatric Blunt Trauma: A Tool for Timing Child Abuse?

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Baxter, Amy L.; Lindberg, Daniel M.; Burke, Bonnie L.; Shults, Justine; Holmes, James F.

2008-01-01

Objectives: Previous research in adult patients with blunt hepatic injuries has suggested a pattern of serum hepatic transaminase concentration decline. Evaluating this decline after pediatric blunt hepatic trauma could establish parameters for estimating the time of inflicted injuries. Deviation from a consistent transaminase resolution pattern…

Protective effect of Mangifera indica L. extract (Vimang) on the injury associated with hepatic ischaemia reperfusion.

Science.gov (United States)

Sánchez, Gregorio Martínez; Rodríguez H, María A; Giuliani, Attilia; Núñez Sellés, Alberto J; Rodríguez, Niurka Pons; León Fernández, Olga Sonia; Re, L

2003-03-01

The effect of Mangifera indica L. extract (Vimang) on treatment of injury associated with hepatic ischaemia/reperfusion was tested. Vimang protects from the oxidative damage induced by oxygen-based free radicals as shown in several in vitro test systems conducted. The ability of Vimang to reduce liver damage was investigated in rats undergoing right-lobe blood fl ow occlusion for 45 min followed by 45 min of reperfusion. The ischaemia/reperfusion model leads to an increase of transaminase (ALT and AST), membrane lipid peroxidation, tissue neutrophil in filtration, DNA fragmentation, loss of protein -SH groups, cytosolic Ca2+ overload and a decrease of catalase activity. Oral administration of Vimang (50, 110 and 250 mg/kg, b.w.) 7 days before reperfusion, reduced transaminase levels and DNA fragmentation in a dose dependent manner (p Vimang also restored the cytosolic Ca2+ levels and inhibited polymorphonuclear migration at a dose of 250 mg/kg b.w., improved the oxidation of total and non protein sulfhydryl groups and prevented modification in catalase activity, uric acid and lipid peroxidation markers (p Vimang could be a useful new natural drug for preventing oxidative damage during hepatic injury associated with free radical generation. Copyright 2003 John Wiley & Sons, Ltd.

Evaluation of hepatic blood flow using 99mTc-GSA in rats with hepatic blood flow manipulation

International Nuclear Information System (INIS)

Hiraguchi, Etsuo

1995-01-01

Blood clearance and hepatic uptake parameters of 99m Tc-DTPA-galactosyl human serum albumin ( 99m Tc-GSA) were evaluated in two groups of rats, normal liver group and CCl 4 induced chronic liver injury group. In each group, four subgroups were classified as follows: simple laparotomy (LAP), hepatic artery ligation (HAL), portal vein ligation (PVL) and both hepatic artery and portal vein ligation (HAL+PVL). 99m Tc-GSA was intravenously injected (50 μg/100 g B.W.) to rats. Heart and liver were targetted as region of interest and time activity curves (TACs) were obtained. The blood clearance parameters (HH4 and Kd) and the hepatic uptake parameters (LHL4 and Ku) were calculated from these TACs. In normal liver group, the mean HH4 of LAP was significantly different from those of PVL and HAL+PVL. Similarly, the other three parameters (LHL4, Kd and Ku) of LAP were significantly different from those of PVL and HAL+PVL. CCl 4 induced chronic liver injury group showed significant difference on all four parameters in four subgroups. Hepatic tissue blood flow rates (HTBFR) calculated by Laser Doppler flowmeter correlated well with 99m Tc-GSA parameters in both groups. These results suggest that 99m Tc-GSA is useful to estimate hepatic blood flow not only in rats with normal liver, but also in rats with CCl 4 induced chronic liver injury. (author)

Professional autobiography of Professor Leif Svanström - with a focus on injury prevention and safety promotion.

Science.gov (United States)

Svanström, Leif

2012-01-01

Professor Svanström has spent about forty-five years in the field of Social Medicine and Health and Safety Promotion. His main lines of research and teaching are Injury Epidemiology and Safety Promotion. In the 1960s, he conducted a number of descriptive and analytical studies, and in the 1970s began to address home and occupational injuries. In 1974, he introduced the community approach to safety promotion, encapsulated in the Falköping Model, which has heavily influenced Swedish and international community safety work. Under his leadership of the Research Group on Injury Prevention and Safety Promotion at the Karolinska Institutet in Stockholm, Sweden, more than 30 doctorates have been awarded. His work as Head of the WHO Collaborating Centre on Community Safety Promotion has led to the establishment of Safe Communities worldwide.

Insulin-like peptide 5 is a microbially regulated peptide that promotes hepatic glucose production

DEFF Research Database (Denmark)

Lee, Ying Shiuan; De Vadder, Filipe; Tremaroli, Valentina

2016-01-01

expression in the brain was higher in CONV-R versus GF mice. We also observed that colonic Insl5 expression was suppressed by increasing the energy supply in GF mice by colonization or high-fat feeding. We did not observe any differences in food intake, gut transit or oral glucose tolerance between Insl5......-/- and wild-type mice. However, we showed impaired intraperitoneal glucose tolerance in Insl5-/- mice. We also observed improved insulin tolerance and reduced hepatic glucose production in Insl5-/- mice. CONCLUSIONS: We have shown that colonic Insl5 expression is regulated by the gut microbiota and energy...... availability. We propose that INSL5 is a hormone that could play a role in promoting hepatic glucose production during periods of energy deprivation....

Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

OpenAIRE

Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

2015-01-01

Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-l...

The utility of CT for predicting bile leaks in hepatic trauma.

Science.gov (United States)

LeBedis, Christina A; Anderson, Stephan W; Mercier, Gustavo; Kussman, Steven; Coleman, Stephanie L; Golden, Louis; Penn, David R; Uyeda, Jennifer W; Soto, Jorge A

2015-04-01

The purpose of this study was to determine the efficacy of CT to predict the development of bile leaks in hepatic trauma. This HIPAA-compliant retrospective study was IRB approved and consent was waived. All patients who sustained hepatic trauma between January 1, 2006, and January 31, 2012, and who underwent CT and hepatobiliary scans during the same hospital admission were included. One hundred and thirty-two patients met the inclusion criteria. Comparison between the presence of biliary injury relative to American Association for the Surgery of Trauma (AAST) hepatic injury grade and mean distance of the hepatic laceration to the inferior vena cava (IVC) was made. The ability of free fluid to predict bile injury was analyzed. Forty-one (31 %) of the 132 patients had positive hepatobiliary scans. Of these 41 patients, seven (17 %) sustained low-grade and 34 (83 %) sustained high-grade hepatic injury compared with the 37 (41 %) low-grade and 54 (59 %) high-grade hepatic injuries in the negative hepatobiliary scan group. The mean distance to the IVC was 2.4 cm (SD 2.9 cm) and 3.6 cm (SD 3.3 cm) in patients with and without bile leaks, respectively. A statistically significant difference in the proportion of high-grade injuries and the mean distance from the IVC between the two groups was identified. The presence of free fluid on CT is sensitive, but not specific, for detecting a bile leak. CT findings, including AAST liver injury grade and location of the liver laceration, are able to predict which patients are at risk for developing bile leaks as seen on hepatobiliary scintigraphy, whereas the presence of free fluid is not.

Orlistat-induced fulminant hepatic failure.

Science.gov (United States)

Sall, D; Wang, J; Rashkin, M; Welch, M; Droege, C; Schauer, D

2014-12-01

Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. © 2014 The Authors. Clinical Obesity © 2014 World Obesity.

Localized fluid collection of hepatic bare area in children with blunt abdominal trauma

Energy Technology Data Exchange (ETDEWEB)

Kim, Myung Gi; Kim, Ji Hyung; Kim, Ok Hwa [School of Medicine, Ajou University, Suwon (Korea, Republic of)

2000-06-01

To investigate the incidence and significance of localized fluid collection in the hepatic bare area resulting from blunt abdominal trauma in children. We retrospectively reviewed the CT scans and medical records of eighty children with blunt abdominal trauma and evaluated the incidence of fluid collection in the hepatic bare area. The findings were correlated with the presence of injury to adjacent organs. Fluid collection in the hepatic bare area was noted in 23 of 80 patients (28.7%). Associated organ injuries included liver laceration (17/23), contusion of the right hemidiaphragm (7/23), right adrenal injury (5/23), and right renal injury (5/23). In one patient, organic injury was not detected in spite of fluid collection in the hepatic bare area. Eight of 23 patients (34.8%) showed fluid collection in this area, but not intraperitoneally. Fluid collection in the hepatic bare area after blunt abdominal trauma was noted in about 30% of patients and was frequently accompanied by injury to adjacent organs. Since right hemidiaphragmatic contusion associated with fluid collection in the bare area was not a uncommon CT finding, close observation of the condition is warranted. (author)

Localized fluid collection of hepatic bare area in children with blunt abdominal trauma

International Nuclear Information System (INIS)

Kim, Myung Gi; Kim, Ji Hyung; Kim, Ok Hwa

2000-01-01

To investigate the incidence and significance of localized fluid collection in the hepatic bare area resulting from blunt abdominal trauma in children. We retrospectively reviewed the CT scans and medical records of eighty children with blunt abdominal trauma and evaluated the incidence of fluid collection in the hepatic bare area. The findings were correlated with the presence of injury to adjacent organs. Fluid collection in the hepatic bare area was noted in 23 of 80 patients (28.7%). Associated organ injuries included liver laceration (17/23), contusion of the right hemidiaphragm (7/23), right adrenal injury (5/23), and right renal injury (5/23). In one patient, organic injury was not detected in spite of fluid collection in the hepatic bare area. Eight of 23 patients (34.8%) showed fluid collection in this area, but not intraperitoneally. Fluid collection in the hepatic bare area after blunt abdominal trauma was noted in about 30% of patients and was frequently accompanied by injury to adjacent organs. Since right hemidiaphragmatic contusion associated with fluid collection in the bare area was not a uncommon CT finding, close observation of the condition is warranted. (author)

Review of liver injury associated with dietary supplements.

Science.gov (United States)

Stickel, Felix; Kessebohm, Kerstin; Weimann, Rosemarie; Seitz, Helmut K

2011-05-01

Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms 'dietary/nutritional supplements', 'adverse hepatic reactions', 'liver injury'; 'hepatitis', 'liver failure', 'vitamin A' and 'retinoids', and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks. © 2011 John Wiley & Sons A/S.

In vivo identification of promoter elements and transcription factors mediating activation of hepatic HMG-CoA reductase by T{sub 3}

Energy Technology Data Exchange (ETDEWEB)

Boone, Lindsey R.; Niesen, Melissa I. [Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL (United States); Jaroszeski, Mark [Department of Chemical and Biomedical Engineering, College of Engineering, University of South Florida, Tampa, FL (United States); Ness, Gene C., E-mail: gness@hsc.usf.edu [Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL (United States)

2009-07-31

The promoter elements and transcription factors necessary for triiodothyronine (T{sub 3}) induction of hepatic HMG-CoA reductase (HMGR) were investigated by transfecting rat livers with wild type and mutant HMGR promoter-luciferase constructs using in vivo electroporation. Mutations in the sterol response element (SRE), nuclear factor-y (NF-Y) site, and the newly identified upstream transcription factor-2 (USF-2) site essentially abolished the T{sub 3} response. Chromatin immunoprecipitation (ChIP) analysis demonstrated that T{sub 3} treatment caused a 4-fold increase in in vivo binding of USF-2 to the HMGR promoter. Co-transfection of the wild type HMGR promoter with siRNAs to USF-2, SREBP-2, or NF-Y nearly abolished the T{sub 3} induction, as measured by promoter activity. These data provide in vivo evidence for functional roles for USF-2, SREBP-2, and NF-Y in mediating the T{sub 3}-induction of hepatic HMGR transcription.

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

International Nuclear Information System (INIS)

Uematsu, Yasuaki; Akai, Sho; Tochitani, Tomoaki; Oda, Shingo; Yamada, Toru; Yokoi, Tsuyoshi

2016-01-01

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

Energy Technology Data Exchange (ETDEWEB)

Uematsu, Yasuaki, E-mail: yasuaki-uematsu@ds-pharma.co.jp [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Akai, Sho [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Tochitani, Tomoaki [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Oda, Shingo [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Yamada, Toru [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Yokoi, Tsuyoshi [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

2016-09-15

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

Computed tomographic diagnosis of the blunt hepatic trauma

International Nuclear Information System (INIS)

Suzuki, Masayuki; Takashima, Tsutomu; Funaki, Hiromi; Kanno, Seiichi; Ushitani, Kenji; Tabuchi, Makoto.

1982-01-01

In this report, the CT appearances of three cases of the blunt hepatic trauma are presented. The hepatic hematomas are displayed as the poorly demarcated, uneven low density area on plain CT. Post-contrast study makes their margin more clearly. The intrapertioneal hemorrhage is shown as a fluid collection around the liver and/or spleen. As CT is non-invasively and quickly performed, it is useful for the evaluation of the hepatic injury in emergency. The concomitant other organ injuries may be accurately detected by CT. The follow-up study is useful for estimating the therapeutic effect and considering the treatment plan. (author)

Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis.

Science.gov (United States)

Ben-Ari, Z; Broida, E; Monselise, Y; Kazatsker, A; Baruch, J; Pappo, O; Skappa, E; Tur-Kaspa, R

2000-03-01

Giant cell hepatitis (GCH) in adults is a rare event. The diagnosis of GCH is based on findings of syncytial giant hepatocytes. It is commonly associated with either viral infection or autoimmune hepatitis type I. A patient with GCH due to autoimmune hepatitis type II (LKM1+) is described, a combination that has not been previously reported. Corticosteroid therapy was effective in decreasing serum liver enzymes; however, the patient deteriorated rapidly and developed subfulminant hepatic failure. Although an emergency orthotopic liver transplantation was performed, the patient died because of reperfusion injury. Interestingly, only a few giant hepatocytes were noted in the explanted liver. This case stresses the association of GCH with autoimmune disorders, the possible immune mechanism involved in the formation of giant cell hepatocytes, and illustrates the rapidly progressive course and unfavorable prognosis that these patients can develop.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

International Nuclear Information System (INIS)

Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Energy Technology Data Exchange (ETDEWEB)

Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

Breath pentane as a potential biomarker for survival in hepatic ischemia and reperfusion injury--a pilot study.

Directory of Open Access Journals (Sweden)

Changsong Wang

Full Text Available BACKGROUND: Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation. METHODOLOGY/PRINCIPAL FINDINGS: Twenty male swine were assigned to two groups: propofol (n = 10 and chloral hydrate groups (n = 10. Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150-360 min in the chloral hydrate group. All of the swine were alive in the propofol group. CONCLUSIONS: Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.

The protective role of nitric oxide and nitric oxide synthases in whole-body hyperthermia-induced hepatic injury in rats.

Science.gov (United States)

Chen, Chao-Fuh; Wang, David; Leu, Fur-Jiang; Chen, Hsing I

2012-01-01

The present study was designed to elucidate the role of endothelial nitric oxide (NO) synthase (eNOS), inducible NOS (iNOS)-derived NO and heat-shock protein (Hsp70) in a rat model of whole-body hyperthermia (WBH)-induced liver injury. Real-time polymerase chain reaction, immunohistochemistry and western blot were used to observe the mRNA and protein expression of eNOS, iNOS and Hsp70. Rats were exposed to hyperthermia by immersion for 60 min at a conscious state in a water bath maintained at 41°C. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were used to assess liver injury 15 h after the hyperthermia challenge. Nitrosative and oxidative mediators, particularly NO and hydroxyl radical were measured. Plasma AST, ALT, hydroxyl radical, and NO were significantly increased after WBH. There were 4.14 ± 0.42, 2.82 ± 0.34 and 2.91 ± 0.16-fold increases in the mRNA expression of eNOS, iNOS and Hsp70. Immunohistochemistry and western blot showed up-regulation of eNOS, iNOS and Hsp70 protein. An eNOS inhibitor (N(ω)-nitro-L-arginine methyl ester (L-NAME)), or an iNOS inhibitor (aminoguanidine (AG)), significantly aggravated the liver injury. On the contrary, administration of NO precursor, L-arginine (L-ARG), attenuated the liver injury. Hsp70 inhibitor quercetin reduced Hsp70, while aggravating the WBH-induced hepatic changes. WBH induces increases in eNOS, iNOS and Hsp70 expression with increase in NO release. The deleterious effects of L-NAME and AG and the protective effects of L-ARG and Hsp70 inhibitor on the liver function and pathology suggest that NO and heat shock protein play a beneficial role in the WBH-induced hepatic injury.

Expression of scavenger receptor‐AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis

Science.gov (United States)

Labonte, Adam C.; Sung, Sun‐Sang J.; Jennelle, Lucas T.; Dandekar, Aditya P.

2016-01-01

The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that expression of C‐type lectin receptor scavenger receptor‐AI (SR‐AI) is crucial for promoting M2‐like Mϕ activation and polarization during hepatic inflammation. Liver Mϕ uniquely up‐regulated SR‐AI during hepatotropic viral infection and displayed increased expression of alternative Mϕ activation markers, such as YM‐1, arginase‐1, and interleukin‐10 by activation of mer receptor tyrosine kinase associated with inhibition of mammalian target of rapamycin. Expression of these molecules was reduced on Mϕ obtained from livers of infected mice deficient for the gene encoding SR‐AI (msr1). Furthermore, in vitro studies using an SR‐AI‐deficient Mϕ cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild‐type (WT) cell line, but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR‐AI–/– mice following hepatic infection and adoptive transfer of WT bone‐marrow–derived Mϕ conferred protection against fibrosis in these mice. Conclusion: SR‐AI expression on liver Mϕ promotes recovery from infection‐induced tissue damage by mediating a switch to a proresolving Mϕ polarization state. (Hepatology 2017;65:32‐43). PMID:27770558

Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions

Science.gov (United States)

Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

2016-01-01

Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy. PMID:27377741

Brief Introduction to Hepatitis B for Parents of Adopted Children

Science.gov (United States)

Brief Introduction to Hepatitis B for Parents of Adopted Children by Sarah Jane Schwarzenberg, MD What is hepatitis B? ... injury will also need careful medical management. In short, prospective par- ents of children with hepatitis B ...

Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

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Huang, Yu, E-mail: 1293363632@QQ.com [Faculty of Graduate Studies of Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China); Deng, Xin, E-mail: Hendly@163.com [Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, 10 East China Road, Nanning 530011, Guangxi Zhuang Autonomous Region (China); Liang, Jian, E-mail: lj99669@163.com [Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China)

2017-03-15

Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are the foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.

Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training.

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Fang Du

Full Text Available This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS, and liver injury improvement by rat-tail suspension with resistance training model (TS&RT. Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM. The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST were significantly higher (p<0.05 in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05 of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR showed that TS rats had higher mRNA levels (P < 0.05 of glucose-regulated protein 78 (GRP78 and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP and c-Jun N-terminal kinase (JNK were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage.

Hepatic enzyme decline after pediatric blunt trauma: a tool for timing child abuse?

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Baxter, Amy L; Lindberg, Daniel M; Burke, Bonnie L; Shults, Justine; Holmes, James F

2008-09-01

Previous research in adult patients with blunt hepatic injuries has suggested a pattern of serum hepatic transaminase concentration decline. Evaluating this decline after pediatric blunt hepatic trauma could establish parameters for estimating the time of inflicted injuries. Deviation from a consistent transaminase resolution pattern could indicate a developing complication. Retrospective review of pediatric patients with injuries including blunt liver trauma admitted to one of four urban level 1 trauma centers from 1990 to 2000. Cases were excluded for shock, death within 48 h, complications, or inability to determine injury time. Transaminase concentration decline was modeled by individual patients, by injury grade, and as a ratio with regard to injury time. One hundred and seventy-six patients met inclusion criteria. The rate of aspartate aminotransferase (AST) clearance changed significantly over time. Alanine aminotransferase (ALT) fell more slowly. Of the 118 patients who had multiple measurements of AST, for 112 (95%) the first concentration obtained was the highest. When ALT was greater than AST, the injury was older than 12h (97% specificity (95% CI, 95-99%), sensitivity 42% (95% CI, 33-50%)). Patients with enzymes that rose after 14 h post-injury were more likely to develop complications (RR=24, 95% CI 10-58). Hepatic transaminases rise rapidly after uncomplicated blunt liver injury, then fall predictably. Persistently stable or increasing concentrations may indicate complications. ALT>AST indicates subacute injury.

Hepatic arterial pseudoaneurysm: a rare complication of blunt abdominal trauma in children

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Basile, K.E.; Sivit, C.J.; Sachs, P.B.; Stallion, A.

1999-01-01

We report a child who developed a hepatic artery pseudoaneurysm following blunt hepatic injury. This is a rare complication of hepatic trauma in children. The imaging evaluation and clinical management of hepatic artery pseudoaneurysms are presented. (orig.)

Parvovirus B19 Associated Hepatitis

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Bihari, Chhagan; Rastogi, Archana; Saxena, Priyanka; Rangegowda, Devraj; Chowdhury, Ashok; Gupta, Nalini; Sarin, Shiv Kumar

2013-01-01

Parvovirus B19 infection can present with myriads of clinical diseases and syndromes; liver manifestations and hepatitis are examples of them. Parvovirus B19 hepatitis associated aplastic anemia and its coinfection with other hepatotropic viruses are relatively underrecognized, and there is sufficient evidence in the literature suggesting that B19 infections can cause a spectrum of liver diseases from elevation of transaminases to acute hepatitis to fulminant liver failure and even chronic hepatitis. It can also cause fatal macrophage activation syndrome and fibrosing cholestatic hepatitis. Parvovirus B19 is an erythrovirus that can only be replicate in pronormoblasts and hepatocytes, and other cells which have globosides and glycosphingolipids in their membrane can also be affected by direct virus injury due to nonstructural protein 1 persistence and indirectly by immune mediated injury. The virus infection is suspected in bone marrow aspiration in cases with sudden drop of hemoglobin and onset of transient aplastic anemia in immunosuppressed or immunocompetent patients and is confirmed either by IgM and IgG positive serology, PCR analysis, and in situ hybridization in biopsy specimens or by application of both. There is no specific treatment for parvovirus B19 related liver diseases, but triple therapy regimen may be effective consisting of immunoglobulin, dehydrohydrocortisone, and cyclosporine. PMID:24232179

O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis.

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Misra, Jagannath; Kim, Don-Kyu; Jung, Yoon Seok; Kim, Han Byeol; Kim, Yong-Hoon; Yoo, Eun-Kyung; Kim, Byung Gyu; Kim, Sunghoon; Lee, In-Kyu; Harris, Robert A; Kim, Jeong-Sun; Lee, Chul-Ho; Cho, Jin Won; Choi, Hueng-Sik

2016-10-01

Estrogen-related receptor γ (ERRγ) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein O-GlcNAcylation. In this study, we demonstrate that ERRγ is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRγ recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRγ ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRγ protein and blocks the ability of ERRγ to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERRγ by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRγ-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRγ serves as a major signal to promote hepatic gluconeogenesis. © 2016 by the American Diabetes Association.

Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock.

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Matheson, Paul J; Hurt, Ryan T; Franklin, Glen A; McClain, Craig J; Garrison, R Neal

2009-10-01

Obese patients (BMI>35) after blunt trauma are at increased risk compared to non-obese for organ dysfunction, prolonged hospital stay, infection, prolonged mechanical ventilation, and mortality. Obesity and non-alcoholic fatty liver disease (NAFLD) produce a low grade systemic inflammatory response syndrome (SIRS) with compromised hepatic blood flow, which increases with body mass index. We hypothesized that obesity further aggravates liver dysfunction by reduced hepatic perfusion following resuscitated hemorrhagic shock (HEM). Age-matched Zucker rats (Obese, 314-519 g & Lean, 211-280 g) were randomly assigned to 4 groups (n = 10-12/group): (1) Lean-Sham; (2) Lean, HEM, and resuscitation (HEM/RES); (3) Obese-Sham; and (4) Obese-HEM/RES. HEM was 40% of mean arterial pressure (MAP) for 60 min; RES was return of shed blood/5 min and 2 volumes of saline/25 min. Hepatic blood flow (HBF) using galactose clearance, liver enzymes and complete metabolic panel were measured over 4 h after completion of RES. Obese rats had increased MAP, heart rate, and fasting blood glucose and BUN concentrations compared to lean controls, required less blood withdrawal (mL/g) to maintain 40% MAP, and RES did not restore BL MAP. Obese rats had decreased HBF at BL and during HEM/RES, which persisted 4 h post RES. ALT and BUN were increased compared to Lean-HEM/RES at 4 h post-RES. These data suggest that obesity significantly contributes to trauma outcomes through compromised vascular control or through fat-induced sinusoidal compression to impair hepatic blood flow after HEM/RES resulting in a greater hepatic injury. The pro-inflammatory state of NAFLD seen in obesity appears to prime the liver for hepatic ischemia after resuscitated hemorrhagic shock, perhaps intensified by insidious and ongoing hepatic hypoperfusion established prior to the traumatic injury or shock.

Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver

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Meiyuan Zhang

2018-06-01

Full Text Available Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15 is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress. Keywords: Fasting, Fatty acid β-oxidation, Ketogenesis, GDF15, XBP1, NAFLD

Carbon monoxide-Releasing Molecule-2 (CORM-2 attenuates acute hepatic ischemia reperfusion injury in rats

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Zhang Weihui

2010-05-01

Full Text Available Abstract Background Hepatic ischemia-reperfusion injury (I/Ri is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO by application of so-called CO-releasing molecules (CORMs. Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model. Methods Forty male Wistar rats were randomly assigned into four groups (n = 10. Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg, which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration. Results A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in

Extrahepatic duct injury in blunt trauma: two case reports and a literature review.

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Zago, Thiago Messias; Pereira, Bruno Monteiro Tavares; Calderan, Thiago Rodrigues Araujo; Hirano, Elcio Shiyoiti; Fraga, Gustavo Pereira

2014-08-01

Traumatic injuries of the extrahepatic biliary tract are rare. Associated injuries are usually responsible for immediate indication for surgical treatment, the time when an injury to the extrahepatic biliary ducts may be diagnosed. However, missed injuries are often common. The primary aim of this paper is to describe the clinical features, diagnosis, treatment, and outcome of two patients with left hepatic duct injury after blunt abdominal trauma. As a secondary objective, a literature review is presented. The two cases presented in this study are as follows: (1) A young male, involved in a motor vehicle crash, was admitted with blunt hepatic trauma in a general hospital. Endoscopic retrograde cholangiography was conducted 3 weeks later and revealed a large leakage at the left hepatic duct. Exploratory laparotomy was performed 26 days after the initial traumatic event and identified a complete section of the left hepatic duct, treated with anastomosis. (2) A male fell from a height. On exploratory laparotomy, a 30 % partial injury of the left hepatic duct was found in addition to hemoperitoneum, liver injury, gallbladder detachment together with cystic duct rupture, retroperitoneal hematoma to the right, and cecum hematoma. A high level of suspicion is necessary to identify injuries to the hepatic ducts. Early diagnosis that occurs during laparotomy due to associated injuries is important to reduce complications.

Injury Based on Its Study in Experimental Models

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M. Mendes-Braz

2012-01-01

Full Text Available The present review focuses on the numerous experimental models used to study the complexity of hepatic ischemia/reperfusion (I/R injury. Although experimental models of hepatic I/R injury represent a compromise between the clinical reality and experimental simplification, the clinical transfer of experimental results is problematic because of anatomical and physiological differences and the inevitable simplification of experimental work. In this review, the strengths and limitations of the various models of hepatic I/R are discussed. Several strategies to protect the liver from I/R injury have been developed in animal models and, some of these, might find their way into clinical practice. We also attempt to highlight the fact that the mechanisms responsible for hepatic I/R injury depend on the experimental model used, and therefore the therapeutic strategies also differ according to the model used. Thus, the choice of model must therefore be adapted to the clinical question being answered.

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

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Li, Xinwei; Huang, Weikun; Gu, Jingmin; Du, Xiliang; Lei, Lin; Yuan, Xue; Sun, Guoquan; Wang, Zhe; Li, Xiaobing; Liu, Guowen

2015-10-01

Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver. Copyright © 2015. Published by Elsevier Inc.

CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells.

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Hou, Xin; Hao, Xiaolei; Zheng, Meijuan; Xu, Congfei; Wang, Jun; Zhou, Rongbin; Tian, Zhigang

2017-08-01

Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection; however, the underlying mechanisms remain obscure. In this study, hepatitis B surface antigen transgenic (HBs-Tg) mice and their wild-type (WT) control C57BL/6 mice were injected with CpG-oligodeoxynucleotides (ODNs) to mimic the translocation of gut microbial products into the systemic circulation. We found that, compared with the WT mice, the HBs-Tg mice were oversensitive to CpG-ODN-induced liver injury, which was dependent on natural killer T (NKT) cells. CpG-ODN injection enhanced the expression of Fas ligand (FasL) on NKT cells. In addition, hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice, which was further augmented by CpG-ODN. Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice. Moreover, Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin (IL)-12 than did those in the WT mice. Finally, the depletion of Kupffer cells, neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited CpG-ODN-induced liver injury and NKT activation in the HBs-Tg mice. Our data suggest that CD205-expressing Kupffer cells respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.

Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

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Zhou, Yan [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Zhou, Lili; Shu, Xugang [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Sun, Xiaohong [College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Mi, Shumei; Yang, Yuhui [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Yin, Yulong, E-mail: yinyulong@isa.ac.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125 (China)

2016-01-22

Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

International Nuclear Information System (INIS)

Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

2016-01-01

Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats

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Ebaid Hossam

2013-02-01

Full Text Available Abstract This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1, interferon gamma (IFN-γ, programmed cell death-receptor (Fas and Tumor necrosis factor-alpha (TNF-α mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA, cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-α and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-γ and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals.

Hepatic arterial pseudoaneurysm: a rare complication of blunt abdominal trauma in children

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Basile, K.E.; Sivit, C.J.; Sachs, P.B. [Department of Radiology, Rainbow Babies and Children`s Hospital of the University Hospitals of Cleveland, OH (United States); Stallion, A. [Department of Surgery, Rainbow Babies` and Children`s Hospital of the University Hospitals of Cleveland, OH (United States)

1999-05-01

We report a child who developed a hepatic artery pseudoaneurysm following blunt hepatic injury. This is a rare complication of hepatic trauma in children. The imaging evaluation and clinical management of hepatic artery pseudoaneurysms are presented. (orig.) With 3 figs., 8 refs.

Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: Preliminary Observations

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Marie Amougou Atsama

2017-11-01

Full Text Available Objectives: To determine the seroprevalence of hepatitis E virus (HEV infection in patients with chronic hepatitis and/or hepatocellular carcinoma (HCC and to assess its potential consequences for disease progression. Methods: We conducted a prospective case-control study on patients with HCC hepatitis B or C related and non-HCC patients including patients with CLD and patients without clinical evidence of liver disease. Anti-HEV IgG and IgM were tested by ELISA using commercially available kits. Liver damage was assessed by alanine aminotransferase, aspartate aminotransferase, platelets and prothrombin measurements. Results: We observed a significant anti-HEV IgG carriage in HCC patients compared to non-HCC subjects with CLD (41.8% vs 12.6%; P = 9.1 E-6; OR = 4.8, 95%CI: 2.3-10.6. HCC patients with HEV infection display more profound alterations of circulating liver enzymes, platelets count and prothrombin time than HCC patients without sero-reactivity to HEV. Conclusion: Overall, this study indicates a high prevalence of HEV infection in Cameroonian patients with CLD and HCC. These data suggest either that patients with liver tumors are more susceptible to hepeviral infection or that, in a tropical context, HEV might promote the progression of liver diseases towards tumor. Keywords: Hepatocellular carcinoma, Hepatitis E, Seroprevalence, Anti-HEV IgG, Anti-HEV IgM

Transcriptional coactivator NT-PGC-1α promotes gluconeogenic gene expression and enhances hepatic gluconeogenesis.

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Chang, Ji Suk; Jun, Hee-Jin; Park, Minsung

2016-10-01

The transcriptional coactivator PGC-1α plays a central role in hepatic gluconeogenesis. We previously reported that alternative splicing of the PGC-1α gene produces an additional transcript encoding the truncated protein NT-PGC-1α NT-PGC-1α is co-expressed with PGC-1α and highly induced by fasting in the liver. NT-PGC-1α regulates tissue-specific metabolism, but its role in the liver has not been investigated. Thus, the objective of this study was to determine the role of hepatic NT-PGC-1α in the regulation of gluconeogenesis. Adenovirus-mediated expression of NT-PGC-1α in primary hepatocytes strongly stimulated the expression of key gluconeogenic enzyme genes (PEPCK and G6Pase), leading to increased glucose production. To further understand NT-PGC-1α function in hepatic gluconeogenesis in vivo, we took advantage of a previously reported FL-PGC-1α -/- mouse line that lacks full-length PGC-1α (FL-PGC-1α) but retains a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α 254 ). In FL-PGC-1α -/- mice, NT-PGC-1α 254 was induced by fasting in the liver and recruited to the promoters of PEPCK and G6Pase genes. The enrichment of NT-PGC-1α 254 at the promoters was closely associated with fasting-induced increase in PEPCK and G6Pase gene expression and efficient production of glucose from pyruvate during a pyruvate tolerance test in FL-PGC-1α -/- mice. Moreover, FL-PGC-1α -/- primary hepatocytes showed a significant increase in gluconeogenic gene expression and glucose production after treatment with dexamethasone and forskolin, suggesting that NT-PGC-1α 254 is sufficient to stimulate the gluconeogenic program in the absence of FL-PGC-1α Collectively, our findings highlight the role of hepatic NT-PGC-1α in stimulating gluconeogenic gene expression and glucose production. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Use of Sengstaken-Blakemore intrahepatic balloon: an alternative for liver-penetrating injuries.

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Fraga, Gustavo Pereira; Zago, Thiago Messias; Pereira, Bruno Monteiro; Calderan, Thiago Rodrigues Araujo; Silveira, Henrique Jose Virgili

2012-09-01

Severe lesions in the liver are associated with a high mortality rate. Alternative surgical techniques such as the use of an intrahepatic balloon may be effective and reduce mortality in severe hepatic lesions. This study aimed to demonstrate the experience of a university hospital in the use of the Sengstaken-Blakemore balloon in patients with transfixing penetrating hepatic injury as an alternative way to treat these challenging injuries. A retrospective study based on the trauma registry of a university hospital was performed. All patients admitted with hepatic penetrating injuries and treated with the Sengstaken-Blakemore balloon within the period 1990-2010 were reviewed. Forty-six patients with transfixing hepatic injuries were treated with the Sengstaken-Blakemore balloon in the study period. The most frequent cause of injury was gunshot wound (87 % of the patients). The mean trauma scores on admission were Revised Trauma Score (RTS) = 7.12 ± 1.46, Injury Severity Score (ISS) = 22.4 ± 9.7, and Abdominal Trauma Index (ATI) = 19.5 ± 11. According to the severity of the hepatic trauma, 71.8 % of patients had grade III, 23.9 % grade IV, and 4.3 % grade V injuries. Associated abdominal injuries were found in 89.1 % of the patients. The most frequent liver-related complications were hepatic abscess postoperative bleeding (8.6 %), biliary fistula (8.6 %), (4.3 %), and biliary peritonitis (2.1 %). Surgical reintervention was necessary in 14 patients (31.1 %). From those 14, only 3 had the balloon removed. The overall morbidity and mortality rates were 56.5 % and 23.9 % (11 patients), respectively. The knowledge of alternative surgical techniques is essential in improving survival in patients with severe penetrating hepatic injuries. The use of intrahepatic balloon is a viable surgical strategy.

The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

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McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

2017-07-07

The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

USP7 Attenuates Hepatic Gluconeogenesis Through Modulation of FoxO1 Gene Promoter Occupancy

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Hall, Jessica A.; Tabata, Mitsuhisa; Rodgers, Joseph T.

2014-01-01

Hepatic forkhead protein FoxO1 is a key component of systemic glucose homeostasis via its ability to regulate the transcription of rate-limiting enzymes in gluconeogenesis. Important in the regulation of FoxO1 transcriptional activity are the modifying/demodifying enzymes that lead to posttranslational modification. Here, we demonstrate the functional interaction and regulation of FoxO1 by herpesvirus-associated ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease, HAUSP), a deubiquitinating enzyme. We show that USP7-mediated mono-deubiquitination of FoxO1 results in suppression of FoxO1 transcriptional activity through decreased FoxO1 occupancy on the promoters of gluconeogenic genes. Knockdown of USP7 in primary hepatocytes leads to increased expression of FoxO1-target gluconeogenic genes and elevated glucose production. Consistent with this, USP7 gain-of-function suppresses the fasting/cAMP-induced activation of gluconeogenic genes in hepatocyte cells and in mouse liver, resulting in decreased hepatic glucose production. Notably, we show that the effects of USP7 on hepatic glucose metabolism depend on FoxO1. Together, these results place FoxO1 under the intimate regulation of deubiquitination and glucose metabolic control with important implication in diseases such as diabetes. PMID:24694308

Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2

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Renwei Huang

2016-01-01

Full Text Available Hepatic stellate cells (HSCs, previously described for liver-specific mesenchymal stem cells (MSCs, appear to contribute to liver regeneration. Microvesicles (MVs are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP or H2O2 treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH in culture medium were also assessed. Results showed that (1 HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2 HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3 HSC-MVs dose-dependently inhibited the APAP/H2O2 induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury.

Trauma surgeons practice what they preach: The NTDB story on solid organ injury management.

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Hurtuk, Michael; Reed, R Lawrence; Esposito, Thomas J; Davis, Kimberly A; Luchette, Fred A

2006-08-01

Recent studies advocate a nonoperative approach for hepatic and splenic trauma. The purpose of this study was to determine whether the literature has impacted surgical practice and, if so, whether or not the overall mortality of these injuries had changed. The American College of Surgeons' National Trauma Data Bank (NTDB 4.0) was analyzed using trauma admission dates ranging from 1994 to 2003. All hepatic and splenic injuries were identified by ICD-9 codes. As renal trauma management has not changed during the study period, renal injuries were included as a control. Nonoperative management (NOM) rates and overall mortality were determined for each organ. Proportions were compared using chi analysis with significance set at p hepatic, 15,960 renal injuries. There was a significant (p hepatic and splenic trauma whereas renal NOM remained stable for the study period. Despite an increase in NOM for splenic and hepatic injuries, mortality has remained unchanged. This study demonstrates that the management of hepatic and splenic injuries has significantly changed in the past 10 years with no appreciable effect on mortality. NOM has become the standard of care for the management of hepatic and splenic trauma. The NTDB can be used to monitor changes in trauma care in response to new knowledge regarding improved outcomes.

Trends in hepatic injury associated with unintentional overdose of paracetamol (Acetaminophen) in products with and without opioid: an analysis using the National Poison Data System of the American Association of Poison Control Centers, 2000-7.

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Bond, G Randall; Ho, Mona; Woodward, Randall W

2012-02-01

Unintended hepatic injury associated with the use of paracetamol (acetaminophen)-containing products has been growing. The aim of the study was to seek a better understanding of the causes of this observation in order to evaluate the potential impact of proposed preventive measures. Retrospective analysis of a large database containing prospectively collected patient exposure data, clinical symptomatology and outcome. The National Poison Data System database for 2000-7 involving exposures to paracetamol and an opioid was obtained and analysed. This dataset was limited to non-suicidal cases in patients 13 years of age and older. For comparison, the parallel, mutually exclusive dataset involving exposures to one or more non-opioid containing paracetamol products was analysed. Trends in the numbers of patients exposed, treated, and mildly and severely injured were obtained and compared with each other and with trends calculated from publicly available data on sales and population. The association of injury with the number of paracetamol-containing products and the reason for taking them were also assessed. Comparators: During the study period, the US population of those 15 years of age and over rose 8.5%; all pharmaceutical-related calls to all US poison centres rose 25%. For the 8-year period from 2001 to 2008, sales of over-the-counter paracetamol products rose 5% (single-ingredient products fell 3%; paracetamol-containing combination cough and cold products rose 11%) and prescription paracetamol combination products rose 67%. Opioids with paracetamol: A total of 119 731 cases were identified, increasing 70% over the period. The exposure merited acetylcysteine treatment in 8995 cases (252% increase). In total, 2729 patients (2.3%) experienced some hepatic injury (500% increase). Minor injuries rose faster than severe injuries (833% vs 280%) and most injuries (73.0%) were from overuse of a single combination product only, but the injury rate increased with use of

Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury.

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Stephen J A Davies

2011-03-01

Full Text Available Repairing trauma to the central nervous system by replacement of glial support cells is an increasingly attractive therapeutic strategy. We have focused on the less-studied replacement of astrocytes, the major support cell in the central nervous system, by generating astrocytes from embryonic human glial precursor cells using two different astrocyte differentiation inducing factors. The resulting astrocytes differed in expression of multiple proteins thought to either promote or inhibit central nervous system homeostasis and regeneration. When transplanted into acute transection injuries of the adult rat spinal cord, astrocytes generated by exposing human glial precursor cells to bone morphogenetic protein promoted significant recovery of volitional foot placement, axonal growth and notably robust increases in neuronal survival in multiple spinal cord laminae. In marked contrast, human glial precursor cells and astrocytes generated from these cells by exposure to ciliary neurotrophic factor both failed to promote significant behavioral recovery or similarly robust neuronal survival and support of axon growth at sites of injury. Our studies thus demonstrate functional differences between human astrocyte populations and suggest that pre-differentiation of precursor cells into a specific astrocyte subtype is required to optimize astrocyte replacement therapies. To our knowledge, this study is the first to show functional differences in ability to promote repair of the injured adult central nervous system between two distinct subtypes of human astrocytes derived from a common fetal glial precursor population. These findings are consistent with our previous studies of transplanting specific subtypes of rodent glial precursor derived astrocytes into sites of spinal cord injury, and indicate a remarkable conservation from rat to human of functional differences between astrocyte subtypes. In addition, our studies provide a specific population of human

A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production.

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Uchio, Ryusei; Higashi, Yohei; Kohama, Yusuke; Kawasaki, Kengo; Hirao, Takashi; Muroyama, Koutarou; Murosaki, Shinji

2017-01-01

Turmeric ( Curcuma longa ) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

Promotion of hepatic preneoplastic lesions in male B6C3F1 mice by unleaded gasoline.

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Standeven, A M; Wolf, D C; Goldsworthy, T L

1995-01-01

In previous studies, unleaded gasoline (UG) vapor was found to be a liver tumor promoter and hepatocarcinogen in female mice, but UG was not a hepatocarcinogen in male mice. However, UG vapor had similar transient mitogenic effects in nonlesioned liver of both male and female mice under the conditions of the cancer bioassay. We used an initiation-promotion protocol to determine whether UG vapor acts as a liver tumor promoter in male mice and to examine proliferative effects that may be critical to tumor development. Twelve-day-old male B6C3F1 mice were injected with N-nitrosodiethylamine (DEN; 5 mg/kg, intraperitoneally) or vehicle. Starting at 5-7 weeks of age, mice were exposed by inhalation 6 hr/day, 5 days/week for 16 weeks to 0 or 2046 ppm of PS-6 blend UG. UG treatment caused a significant 2.3-fold increase in the number of macroscopic hepatic masses in DEN-initiated mice, whereas no macroscopic masses were observed in non-initiated mice. Altered hepatic foci (AHF), which were predominantly basophilic in phenotype, were found almost exclusively in DEN-initiated mice. UG treatment significantly increased both the mean volume (threefold) and the volume fraction (twofold) of the AHF without increasing the number of AHF per unit area. UG also induced hepatic pentoxyresorufin-O-dealkylase (PROD) activity, a marker of CYP2B, by more than 12-fold over control with or without DEN cotreatment. To study hepatocyte proliferative effects of UG, we treated mice with 5-bromo-2'-deoxyuridine (BrdU) via osmotic pump for 3 days before necropsy and measured hepatocyte BrdU labeling index (LI) in AHF and nonlesioned liver.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. PMID:7588481

The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury

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Tauchi Ryoji

2012-03-01

Full Text Available Abstract Background Chondroitin sulfate proteoglycans are major inhibitory molecules for neural plasticity under both physiological and pathological conditions. The chondroitin sulfate degrading enzyme chondroitinase ABC promotes functional recovery after spinal cord injury, and restores experience-dependent plasticity, such as ocular dominance plasticity and fear erasure plasticity, in adult rodents. These data suggest that the sugar chain in a proteoglycan moiety is essential for the inhibitory activity of proteoglycans. However, the significance of the core protein has not been studied extensively. Furthermore, considering that chondroitinase ABC is derived from bacteria, a mammalian endogenous enzyme which can inactivate the proteoglycans' activity is desirable for clinical use. Methods The degradation activity of ADAMTS-4 was estimated for the core proteins of chondroitin sulfate proteoglycans, that is, brevican, neurocan and phosphacan. To evaluate the biological significance of ADMATS-4 activity, an in vitro neurite growth assay and an in vivo neuronal injury model, spinal cord contusion injury, were employed. Results ADAMTS-4 digested proteoglycans, and reversed their inhibition of neurite outgrowth. Local administration of ADAMTS-4 significantly promoted motor function recovery after spinal cord injury. Supporting these findings, the ADAMTS-4-treated spinal cord exhibited enhanced axonal regeneration/sprouting after spinal cord injury. Conclusions Our data suggest that the core protein in a proteoglycan moiety is also important for the inhibition of neural plasticity, and provides a potentially safer tool for the treatment of neuronal injuries.

Molecular basis of hepatic fibrosis and current status of its diagnosis and treatment

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LI Yan

2018-01-01

Full Text Available During the process of acute or chronic liver injury, hepatic stellate cells interact with various types of cells such as hepatic parenchymal cells, Kupffer cells, and liver sinusoidal endothelial cells to mediate extracellular matrix deposition and sinusoid capillarization and thus initiate the process of hepatic fibrosis. The nature of hepatic fibrosis is repair response after liver injury. Liver biopsy is regarded as the gold standard for the diagnosis of hepatic fibrosis; however, it is generally associated with the risk of bleeding and even death. Noninvasive diagnostic methods for liver fibrosis mainly include serum biomarkers, imaging techniques, and predictive statistical model, but such methods cannot completely replace liver biopsy. At present, the treatment of hepatic fibrosis focuses on the research and development of new drugs targeting primary disease, hepatic stellate cells, or balance of extracellular matrix synthesis/degradation. The research on the molecular mechanism of hepatic fibrosis provides a solid theoretical basis for exploring the treatment of hepatic fibrosis.

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

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Edith Hochhauser

2015-07-01

Full Text Available Background/Aims: Ischemia/reperfusion (I/R injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC, a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70% ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway, the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation. This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. Conclusion: A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.

Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.

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Kitamura, Kazuya; Fujiyoshi, Kanehiro; Yamane, Jun-Ichi; Toyota, Fumika; Hikishima, Keigo; Nomura, Tatsuji; Funakoshi, Hiroshi; Nakamura, Toshikazu; Aoki, Masashi; Toyama, Yoshiaki; Okano, Hideyuki; Nakamura, Masaya

2011-01-01

Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.

Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.

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Kazuya Kitamura

Full Text Available Many therapeutic interventions for spinal cord injury (SCI using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF, which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.

Hepatic Sinusoidal-obstruction Syndrome and Busulfan-induced Lung Injury in a Post-autologous Stem Cell Transplant Recipient.

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Jain, Richa; Gupta, Kirti; Bhatia, Anmol; Bansal, Arun; Bansal, Deepak

2017-09-15

Veno-occlusive disease of the liver is mostly encountered as a complication of hematopoietic stem cell transplantation with myeloablative regimens with an incidence estimated to be 13.7%. It is clinically characterized by tender hepatomegaly, jaundice, weight gain and ascites. Strong clinical suspicion and an early recognition of clinical signs are essential to establish the diagnosis and institute effective regimen. Another complication of cytotoxic drugs given for cancers, is development of busulfan-induced lung injury. A strong index of suspicion is needed for its diagnosis, especially in setting where opportunistic fungal and viral infections manifest similarly. We illustrate the clinical and autopsy finings in a 2½-year-old boy who received autologous stem-cell transplantation following resection of stage IV neuroblastoma. He subsequently developed both hepatic veno-occlusive disease and busulfan-induced lung injury. The autopsy findings are remarkable for their rarity.

Physical activity promotion for people with spinal cord injury: physiotherapists' beliefs and actions.

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Williams, Toni L; Smith, Brett; Papathomas, Anthony

2018-01-01

It is vital that people with spinal cord injury (SCI) lead a physically active lifestyle to promote long term health and well-being. Yet within rehabilitation and upon discharge into the community, people with SCI are largely inactive. Physiotherapists are well placed to promote a physically active lifestyle and are valued and trusted messengers of physical activity (PA) by people with SCI. Therefore this study aimed to explore the perceptions of physiotherapists in SCI rehabilitation on PA for people with SCI, and what is done to promote PA. Semi-structured interviews were completed with 18 neurological physiotherapists (2-22 years experience) from SCI centres in the United Kingdom and Ireland. Framed by interpretivism, an inductive thematic analysis was conducted. Three themes were identified: (1) perceived importance of PA; (2) inconsistent PA promotion efforts; and (3) concern regarding community PA. This article makes a significant contribution to the literature by identifying that although physiotherapists value PA, active promotion of PA remains largely absent from their practice. To enable physiotherapists to promote and prescribe PA as a structured and integral component of their practice, effective knowledge strategies need designing and implementing at the macro, meso, and micro levels of healthcare. Implications for Rehabilitation Physiotherapists are well placed to promote a physically active lifestyle and are perceived as valued and trusted messengers of physical activity (PA). The importance of PA for patients with spinal cord injury (SCI) is valued by physiotherapists yet PA promotion is largely absent from their practice. Physiotherapists lack specific education and training on PA and SCI and hold certain beliefs which restrict their promotion of PA. Knowledge translation across the macro, meso, and micro levels of healthcare are essential to facilitate effective PA promotion.

Balanced management of hepatic trauma is associated with low liver-related mortality.

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Benckert, Christoph; Thelen, Armin; Gaebelein, Gereon; Hepp, Pierre; Josten, Christoph; Bartels, Michael; Jonas, Sven

2010-04-01

Hepatic trauma is a rare surgical emergency with significant morbidity and mortality. Therapeutic strategies have been controversially discussed during the last decades. The medical records of 47 consecutive patients with hepatic trauma treated at the University Hospital of Leipzig between 2004 and 2008 were retrospectively reviewed for the severity of liver injury, management, morbidity, and mortality and compared to a preceding cohort. Logistic regression analysis was performed to identify risk factors influencing mortality. Compared to 63 patients treated between 1993 and 2003, moderate liver injuries (grades I-III) occurred more frequently (p = 0.0006), and the proportion of patients that were managed operatively decreased from 68.9% to 37.5%. Twenty patients (42.6%) were treated conservatively (all grades I to III) and 27 surgically (47.4%). In detail, five patients were treated by hepatic packing alone, 13 by suture or coagulation, five by atypical resection, and four by hemihepatectomy. The overall mortality was 8.5% with a liver-related mortality rate of 2.1%. According to severity grades I-III, IV, and V, mortality rates were 0%, 18.2%, and 50.0%, respectively. Univariate analysis identified Injury Severity Score (ISS) >30, Moore grades IV and V, hemoglobin at admission 12 erythrocyte concentrates to be significant risk factors for early posttraumatic death, while multivariate analysis only ISS >30 revealed to be of prognostic significance for early postoperative survival. Compared to a previous cohort in the same hospital, more patients were treated conservatively. Management of liver injuries presented with a low liver-related mortality rate. Grades I-III injuries can safely be treated by conservative means with excellent results. However, complex hepatic injuries may often require surgical treatment ranging from packing to complex hemihepatectomy. Hence, for selection of appropriate therapeutic options, patients with hepatic injuries should be treated

Does chronic hepatitis B infection affect the clinical course of acute hepatitis A?

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Shin, Su Rin; Moh, In Ho; Jung, Sung Won; Kim, Jin Bae; Park, Sang Hoon; Kim, Hyoung Su; Jang, Myung Kuk; Lee, Myung Seok

2013-01-01

The impact of chronic hepatitis B on the clinical outcome of acute hepatitis A remains controversial. The aim of present study was to evaluate the clinical characteristics of acute hepatitis A in cases with underlying chronic hepatitis B compared to cases of acute hepatitis A alone. Data on 758 patients with acute hepatitis A admitted at two university-affiliated hospitals were reviewed. Patients were classified into three groups: group A, patients with both acute hepatitis A and underlying chronic hepatitis B (n = 27); group B, patients infected by acute hepatitis A alone whose sexes and ages were matched with patients in group A (n  = 54); and group C, patients with acute hepatitis A alone (n = 731). None of the demographic features of group A were significantly different from those of group B or C, except for the proportion of males and body weight, which differed from group C. When comparing to group B, clinical symptoms were more frequent, and higher total bilirubin and lower albumin levels were observed in group A. When comparing to group C, the albumin levels were lower in group A. There were no differences in the duration of hospital stay, occurrence of acute kidney injury, acute liver failure, prolonged cholestasis, or relapsing hepatitis. This study revealed that clinical symptoms and laboratory findings were less favorable for patients with acute hepatitis A and chronic hepatitis B compared to those with acute hepatitis A alone. However, there were no differences in fatal outcomes or serious complications. Copyright © 2012 Wiley Periodicals, Inc.

Recent advances in hepatic encephalopathy

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DeMorrow, Sharon

2017-01-01

Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy. A literature search using the PubMed database was conducted in May 2017 using “hepatic encephalopathy” as a keyword, and selected manuscripts were limited to those research articles published since May 2014. While the authors acknowledge that many significant advances have been made in the understanding of hepatic encephalopathy prior to May 2014, we have limited the scope of this review to the previous three years only. PMID:29026534

Young People's Safety Beliefs after a Spinal Cord Injury Health Promotion and Awareness Presentation

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Watling, David P.; Bishara, Jason D.; Zeeman, Heidi

2018-01-01

Objective: Adolescence is presented as a vulnerable period for accidental injury, particularly spinal cord injury, given young people's propensity for risky behaviours. School-based health promotion initiatives provide opportunities for education about the risks associated with dangerous behaviours. In this study, we aimed to describe young…

Nonoperative management of blunt hepatic trauma: A systematic review.

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Boese, Christoph Kolja; Hackl, Michael; Müller, Lars Peter; Ruchholtz, Steffen; Frink, Michael; Lechler, Philipp

2015-10-01

Nonoperative management (NOM) has become the standard treatment in hemodynamically stable patients with blunt hepatic injuries. While the reported overall success rates of NOM are excellent, there is a lack of consensus regarding the risk factors predicting the failure of NOM. The aim of this systematic review was to identify the incidence and prognostic factors for failure of NOM in adult patients with blunt hepatic trauma. Prospective studies reporting prognostic factors for the failure of nonoperative treatment of blunt liver injuries were identified by searching MEDLINE and the Cochrane Central Register of Controlled Trials. We screened 798 titles and abstracts, of which 8 single-center prospective observational studies, reporting 410 patients, were included in the qualitative and quantitative synthesis. No randomized controlled trials were found. The pooled failure rate of NOM was 9.5% (0-24%). Twenty-six prognostic factors predicting the failure of NOM were reported, of which six reached statistical significance in one or more studies: blood pressure (p hepatic injuries. Systematic review, level III.

Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation.

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Golden-Mason, Lucy; Rosen, Hugo R

2017-07-01

Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279). © 2017 by the American Association for the Study of Liver Diseases.

ASS and SULT2A1 are Novel and Sensitive Biomarkers of Acute Hepatic Injury-A Comparative Study in Animal Models.

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Prima, Victor; Cao, Mengde; Svetlov, Stanislav I

2013-01-10

Liver and kidney damage associated with polytrauma, endotoxic shock/sepsis, and organ transplantation, are among the leading causes of the multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver and kidney injury is vital for the effective diagnostics and treatment of these life-threatening conditions. Previously, we identified several hepatic proteins, including Argininosuccinate Synthase (ASS) and sulfotransferases which were degraded in the liver and rapidly released into circulation during Ischemia/Reperfusion (I/R) injury. Here we compared sensitivity and specificity of the newly developed sandwich ELISA assays for ASS and the sulfotransferase isoform SULT2A1 with the standard clinical liver and kidney tests Alanine Aminotransferase (ALT) and Aspartate Transaminase (AST) in various pre-clinical models of acute injury. Our data suggest that ASS and SULT2A1 have superior characteristics for liver and kidney health assessment in endotoxemia, Ischemia/Reperfusion (I/R), chemical and drug-induced liver injury and may be of high potential value for clinical applications.

Urological injuries following trauma

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Bent, C.; Iyngkaran, T.; Power, N.; Matson, M.; Hajdinjak, T.; Buchholz, N.; Fotheringham, T.

2008-01-01

Blunt renal trauma is the third most common injury in abdominal trauma following splenic and hepatic injuries, respectively. In the majority, such injuries are associated with other abdominal organ injuries. As urological injuries are not usually life-threatening, and clinical signs and symptoms are non-specific, diagnosis is often delayed. We present a practical approach to the diagnosis and management of these injuries based on our experience in a busy inner city trauma hospital with a review of the current evidence-based practice. Diagnostic imaging signs are illustrated

Urological injuries following trauma

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Bent, C. [Department of Diagnostic Imaging, Barts and The London NHS Trust, London (United Kingdom)], E-mail: clare.bent@bartsandthelondon.nhs.uk; Iyngkaran, T.; Power, N.; Matson, M. [Department of Diagnostic Imaging, Barts and The London NHS Trust, London (United Kingdom); Hajdinjak, T.; Buchholz, N. [Department of Urology, Barts and The London NHS Trust, London (United Kingdom); Fotheringham, T. [Department of Diagnostic Imaging, Barts and The London NHS Trust, London (United Kingdom)

2008-12-15

Blunt renal trauma is the third most common injury in abdominal trauma following splenic and hepatic injuries, respectively. In the majority, such injuries are associated with other abdominal organ injuries. As urological injuries are not usually life-threatening, and clinical signs and symptoms are non-specific, diagnosis is often delayed. We present a practical approach to the diagnosis and management of these injuries based on our experience in a busy inner city trauma hospital with a review of the current evidence-based practice. Diagnostic imaging signs are illustrated.

Urological injuries following trauma.

Science.gov (United States)

Bent, C; Iyngkaran, T; Power, N; Matson, M; Hajdinjak, T; Buchholz, N; Fotheringham, T

2008-12-01

Blunt renal trauma is the third most common injury in abdominal trauma following splenic and hepatic injuries, respectively. In the majority, such injuries are associated with other abdominal organ injuries. As urological injuries are not usually life-threatening, and clinical signs and symptoms are non-specific, diagnosis is often delayed. We present a practical approach to the diagnosis and management of these injuries based on our experience in a busy inner city trauma hospital with a review of the current evidence-based practice. Diagnostic imaging signs are illustrated.

How Does the Severity of Injury Vary between Motorcycle and Automobile Accident Victims Who Sustain High-Grade Blunt Hepatic and/or Splenic Injuries? Results of a Retrospective Analysis.

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Hsieh, Ting-Min; Tsai, Tsung-Cheng; Liu, Yueh-Wei; Hsieh, Ching-Hua

2016-07-21

High-grade blunt hepatic and/or splenic injuries (BHSI) remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of traumatic injuries in a Level I trauma center in southern Taiwan. High-grade BHSI are defined as grade III-VI blunt hepatic injuries and grade III-V blunt splenic injuries. This retrospective study reviewed the data of 101 motorcyclists and 32 car occupants who experienced a high-grade BHSI from 1 January 2011 to 31 December 2013. Two-sided Fisher's exact or Pearson's chi-square tests were used to compare categorical data, unpaired Student's t-test was used to analyze normally distributed continuous data, and Mann-Whitney's U test was used to compare non-normally distributed data. In this study, the majority (76%, 101/133) of high-grade BHSI were due to motorcycle crashes. Car occupants had a significantly higher injury severity score (ISS; 26.8 ± 10.9 vs. 20.7 ± 10.4, respectively, p = 0.005) and organ injured score (OIS; 3.8 ± 1.0 vs. 3.4 ± 0.6, respectively, p = 0.033), as well as a significantly longer hospital length of stay (LOS; 21.2 days vs. 14.6 days, respectively, p = 0.038) than did motorcyclists. Car occupants with high-grade BHSI also had worse clinical presentations than their motorcyclist counterparts, including a significantly higher incidence of hypotension, hyperpnea, tube thoracostomy, blood transfusion >4 units, LOS in intensive care unit >5 days, and complications. However, there were no differences in the percentage of angiography or laparotomy performed or mortality rate between these two groups of patients. This study demonstrated that car occupants with high-grade BHSI were injured more severely, had a higher incidence of worse clinical presentation, had a longer hospital LOS, and had a higher incidence of complications than motorcyclists. The results also

How Does the Severity of Injury Vary between Motorcycle and Automobile Accident Victims Who Sustain High-Grade Blunt Hepatic and/or Splenic Injuries? Results of a Retrospective Analysis

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Ting-Min Hsieh

2016-07-01

Full Text Available Background: High-grade blunt hepatic and/or splenic injuries (BHSI remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of traumatic injuries in a Level I trauma center in southern Taiwan. Methods: High-grade BHSI are defined as grade III-VI blunt hepatic injuries and grade III-V blunt splenic injuries. This retrospective study reviewed the data of 101 motorcyclists and 32 car occupants who experienced a high-grade BHSI from 1 January 2011 to 31 December 2013. Two-sided Fisher’s exact or Pearson’s chi-square tests were used to compare categorical data, unpaired Student’s t-test was used to analyze normally distributed continuous data, and Mann–Whitney’s U test was used to compare non-normally distributed data. Results: In this study, the majority (76%, 101/133 of high-grade BHSI were due to motorcycle crashes. Car occupants had a significantly higher injury severity score (ISS; 26.8 ± 10.9 vs. 20.7 ± 10.4, respectively, p = 0.005 and organ injured score (OIS; 3.8 ± 1.0 vs. 3.4 ± 0.6, respectively, p = 0.033, as well as a significantly longer hospital length of stay (LOS; 21.2 days vs. 14.6 days, respectively, p = 0.038 than did motorcyclists. Car occupants with high-grade BHSI also had worse clinical presentations than their motorcyclist counterparts, including a significantly higher incidence of hypotension, hyperpnea, tube thoracostomy, blood transfusion >4 units, LOS in intensive care unit >5 days, and complications. However, there were no differences in the percentage of angiography or laparotomy performed or mortality rate between these two groups of patients. Conclusions: This study demonstrated that car occupants with high-grade BHSI were injured more severely, had a higher incidence of worse clinical presentation, had a longer hospital LOS, and had a

Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.

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Volarevic, Vladislav; Markovic, Bojana Simovic; Bojic, Sanja; Stojanovic, Maja; Nilsson, Ulf; Leffler, Hakon; Besra, Gurdyal S; Arsenijevic, Nebojsa; Paunovic, Verica; Trajkovic, Vladimir; Lukic, Miodrag L

2015-02-01

Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Scanning in the diagnosis of hepatic and splenic trauma

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Fitzer, P.M.

1976-01-01

The diagnosis of hepatic and splenic injuries in the trauma patient with classic physical and plain film findings usually presents little problem. If bleeding is severe there is no time for extensive roentgenographic or laboratory studies. Often, however, the trauma is mild, and the physical findings quite minimal at best. Other injuries may divert attention. The patient may be unconscious. In such circumstances, clinical evaluation of possible hepatic or splenic injuries is difficult. Scanning of the liver and spleen is a safe, accurate, noninvasive, readily available technique for the detection of traumatic rupture, laceration, or hematoma. This report describes two cases in which scanning proved helpful in the management of blunt abdominal trauma

The role of non-operative management (NOM in blunt hepatic trauma

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Ayman Zaki Azzam

2013-09-01

Full Text Available Background: NOM in blunt hepatic trauma is the preferred treatment in otherwise stable patients. Aim: To evaluate the role of NOM in blunt hepatic trauma, avoiding unnecessary surgery. Methods and patients: Forty-four patients who presented with blunt hepatic trauma were admitted to the Emergency Unit. The patients were evaluated clinically. Abdominal computerized tomography was done to all hemodynamically stable patients and who were stabilized by the initial resuscitation. Staging of liver injury was done according to the scoring of the American Association for the Surgery of Trauma (AAST. Initially, all patients were treated conservatively and the patients who needed laparotomy later were considered as failure of NOM. Liver injuries due to penetrating causes were excluded. An informed consent was taken from each patient. Results: Blunt trauma was the mechanism of injury in 44 patients (60.2% including road traffic accidents in 42.5%. The peak age was between 20 and 30 years. The male to female ratio was 10:1. The majority of patients have multiple injuries with 10% having isolated liver injury. Thirty-six patients (82% had one or more associated extra-abdominal injuries. Surgery was indicated in 14 patients (32%. The mean admission systolic pressure was lower in the NOM failure group (90 vs. 122 mmHg with p < 0.04. Complications occurred more in the operative group, chest infection occurred in 21.4% with a p value of 0.001, hyperpyrexia occurred in 21.4% with a p value of 0.001, and wound infection in 14.2% with a p value of 0.025. Mortality occurred in 7 patients. The cause of death in patients with blunt hepatic trauma was liver related in 2 patients due to hemorrhage and DIC. Conclusion: NOM in blunt hepatic trauma is the preferred treatment in otherwise stable patients. The factors that can suspect failure of NOM were the development of hemodynamic instability or the presence of associated injury that mandates immediate exploration

Hepatitis Bx Antigen Stimulates Expression of a Novel Cellular Gene, URG4, that Promotes Hepatocellular Growth and Survival

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N. Lale Satiroglu Tufan

2002-01-01

Full Text Available Hepatitis B virus encoded X antigen (HBxAg may contribute to the development of hepatocellular carcinoma (HCC by up-or downregulating the expression of cellular genes that promote cell growth and survival. To test this hypothesis, HBxAg-positive and-negative HepG2 cells were constructed, and the patterns of cellular gene expression compared by polymerase chain reaction select cDNA subtraction. The full-length clone of one of these upregulated genes (URG, URG4, encoded a protein of about 104 kDa. URG4 was strongly expressed in hepatitis 13-infected liver and in HCC cells, where it costained with HBxAg, and was weakly expressed in uninfected liver, suggesting URG4 was an effector of HBxAg in vivo. Overexpression of URG4 in HepG2 cells promoted hepatocellular growth and survival in tissue culture and in soft agar, and accelerated tumor development in nude mice. Hence, URG4 may be a natural effector of HBxAg that contributes importantly to multistep hepatocarcinogenesis.

Fatty acid translocase promoted hepatitis B virus replication by upregulating the levels of hepatic cytosolic calcium.

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Huang, Jian; Zhao, Lei; Yang, Ping; Chen, Zhen; Ruan, Xiong Z; Huang, Ailong; Tang, Ni; Chen, Yaxi

2017-09-15

Hepatitis B virus (HBV) is designated a "metabolovirus" due to the intimate connection between the virus and host metabolism. The nutrition state of the host plays a relevant role in the severity of HBV infection. Metabolic syndrome (MS) is prone to increasing HBV DNA loads and accelerating the progression of liver disease in patients with chronic hepatitis B (CHB). Cluster of differentiation 36 (CD36), also named fatty acid translocase, is known to facilitate long-chain fatty acid uptake and contribute to the development of MS. We recently found that CD36 overexpression enhanced HBV replication. In this study, we further explored the mechanism by which CD36 overexpression promotes HBV replication. Our data showed that CD36 overexpression increased HBV replication, and CD36 knockdown inhibited HBV replication. RNA sequencing found some of the differentially expressed genes were involved in calcium ion homeostasis. CD36 overexpression elevated the cytosolic calcium level, and CD36 knockdown decreased the cytosolic calcium level. Calcium chelator BAPTA-AM could override the HBV replication increased by CD36 overexpression, and the calcium activator thapsigargin could improve the HBV replication reduced by CD36 knockdown. We further found that CD36 overexpression activated Src kinase, which plays an important role in the regulation of the store-operated Ca 2+ channel. An inhibitor of Src kinase (SU6656) significantly reduced the CD36-induced HBV replication. We identified a novel link between CD36 and HBV replication, which is associated with cytosolic calcium and the Src kinase pathway. CD36 may represent a potential therapeutic target for the treatment of CHB patients with MS. Copyright © 2017 Elsevier Inc. All rights reserved.

Spinal cord injury triggers an intrinsic growth-promoting state in nociceptors.

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Bedi, Supinder S; Lago, Michael T; Masha, Luke I; Crook, Robyn J; Grill, Raymond J; Walters, Edgar T

2012-03-20

Although most investigations of the mechanisms underlying chronic pain after spinal cord injury (SCI) have examined the central nervous system (CNS), recent studies have shown that nociceptive primary afferent neurons display persistent hyperexcitability and spontaneous activity in their peripheral branches and somata in dorsal root ganglia (DRG) after SCI. This suggests that SCI-induced alterations of primary nociceptors contribute to central sensitization and chronic pain after SCI. Does SCI also promote growth of these neurons' fibers, as has been suggested in some reports? The present study tests the hypothesis that SCI induces an intrinsic growth-promoting state in DRG neurons. This was tested by dissociating DRG neurons 3 days or 1 month after spinal contusion injury at thoracic level T10 and measuring neuritic growth 1 day later. Neurons cultured 3 days after SCI exhibited longer neurites without increases in branching ("elongating growth"), compared to neurons from sham-treated or untreated (naïve) rats. Robust promotion of elongating growth was found in small and medium-sized neurons (but not large neurons) from lumbar (L3-L5) and thoracic ganglia immediately above (T9) and below (T10-T11) the contusion site, but not from cervical DRG. Elongating growth was also found in neurons immunoreactive to calcitonin gene-related peptide (CGRP), suggesting that some of the neurons exhibiting enhanced neuritic growth were nociceptors. The same measurements made on neurons dissociated 1 month after SCI revealed no evidence of elongating growth, although evidence for accelerated initiation of neurite outgrowth was found. Under certain conditions this transient growth-promoting state in nociceptors might be important for the development of chronic pain and hyperreflexia after SCI.

NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.

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Yang, Weili; Wang, Junpei; Chen, Zhenzhen; Chen, Ji; Meng, Yuhong; Chen, Liming; Chang, Yongsheng; Geng, Bin; Sun, Libo; Dou, Lin; Li, Jian; Guan, Youfei; Cui, Qinghua; Yang, Jichun

2017-07-01

Hepatic FAM3A expression is repressed under obese conditions, but the underlying mechanism remains unknown. This study determined the role and mechanism of miR-423-5p in hepatic glucose and lipid metabolism by repressing FAM3A expression. miR-423-5p expression was increased in the livers of obese diabetic mice and in patients with nonalcoholic fatty liver disease (NAFLD) with decreased FAM3A expression. miR-423-5p directly targeted FAM3A mRNA to repress its expression and the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic miR-423-5p inhibition suppressed gluconeogenesis and improved insulin resistance, hyperglycemia, and fatty liver in obese diabetic mice. In contrast, hepatic miR-423-5p overexpression promoted gluconeogenesis and hyperglycemia and increased lipid deposition in normal mice. miR-423-5p inhibition activated the FAM3A-ATP-Akt pathway and repressed gluconeogenic and lipogenic gene expression in diabetic mouse livers. The miR-423 precursor gene was further shown to be a target gene of NFE2, which induced miR-423-5p expression to repress the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic NFE2 overexpression upregulated miR-423-5p to repress the FAM3A-ATP-Akt pathway, promoting gluconeogenesis and lipid deposition and causing hyperglycemia in normal mice. In conclusion, under the obese condition, activation of the hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing the FAM3A-ATP-Akt signaling pathway. © 2017 by the American Diabetes Association.

Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

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Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

2015-01-01

Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats. PMID:26487860

Development of a murine model of blunt hepatic trauma.

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Nemzek-Hamlin, Jean A; Hwang, Haejin; Hampel, Joseph A; Yu, Bi; Raghavendran, Krishnan

2013-10-01

Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses. We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine-xylazine-buprenorphine and placed in left lateral recumbency. A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. An impact velocity of 6 m/s and a piston depth of 12 mm produced a consistent pattern of hepatic injury with low mortality. All mice that recovered from anesthesia survived without complication for the length of the study. Mice were euthanized at various time points (n = 5 per group) until 7 d after injury for gross examination and collection of blood and peritoneal lavage fluids. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI. At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 2 h after trauma, there were significant increases in plasma IL10 as well as peritoneal lavage fluid IL6 and CXCL1/KC; however, these levels decreased within 24 h. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size. In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response.

Facial Sports Injuries

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... the patient has HIV or hepatitis. Facial Fractures Sports injuries can cause potentially serious broken bones or fractures of the face. Common symptoms of facial fractures include: swelling and bruising, ...

As bases experimentais da lesão por isquemia e reperfusão do fígado: revisão The experimental basis of hepatic ischemia-reperfusion injury: review

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Luiz Eduardo C. Miranda

2004-01-01

Full Text Available O transplante hepático tornou-se o procedimento de escolha para o tratamento da doença hepática terminal. Não obstante o sucesso da cirurgia, a disfunção pós-operatória do fígado enxertado ainda representa importante causa de morbidade e mortalidade. O restabelecimento do fluxo sangüíneo ao fígado recém transplantado impõe a ele nova agressão, agravando a lesão causada pelo período de isquemia. Este fenômeno pouco compreendido é conhecido como lesão por isquemia e reperfusão e envolve disfunção endotelial, seqüestro de leucócitos e agregação de plaquetas, lesão por radicais livre de oxigênio, e distúrbios da microcirculação hepática. Essa revisão discute os vários aspectos fisiopatológicos que estão envolvidos na lesão por isquemia e reperfusão do fígado.Hepatic transplantation has become the main treatment for patients with terminal hepatic disease. Whatever the success of such surgery, the hepatic dysfunction associated with liver transplantation is an important cause of morbidity and mortality. Paradoxically, on restoring the blood supply, the liver is subjected to a further insult, aggravating the injury already caused by ischemia. This complex phenomenon is termed ischemia-reperfusion injury and involves endothelial cell dysfunction, leukocyte entrapment, platelet aggregation, oxidant stress and hepatic microcirculatory perfusion failure. This review discusses the physiopathlogicals mechanisms of liver ischemia-reperfusion injury.

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

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Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

2014-01-01

Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.

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Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S; Hollingsworth, John W; Jiang, Dianhua; Lancaster, Lisa H; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K; Noble, Paul W; Kimata, Koji; Schwartz, David A

2008-11-01

The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury.

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Arya J Bahrami

Full Text Available 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.

Comparison of gray-scale contrast-enhanced ultrasonography with contrast-enhanced computed tomography in different grading of blunt hepatic and splenic trauma: an animal experiment.

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Tang, Jie; Li, Wenxiu; Lv, Faqin; Zhang, Huiqin; Zhang, Lihai; Wang, Yuexiang; Li, Junlai; Yang, Li

2009-04-01

To compare the diagnostic value of contrast-enhanced ultrasonography (CEUS) with contrast-enhanced computed tomography (CECT) for the detection of different grading of solid organ injuries in blunt abdominal trauma in animals. A self-made miniature tools were used as models to simulate a blunt hepatic or splenic trauma in 16 and 14 anesthetized dogs, respectively. Baseline ultrasound, CEUS and CECT were used to detect traumatic injuries of livers and spleens. The degree of injuries was determined by CEUS according to the American Association for the Surgery of Trauma (AAST) scale and the results compared with injury scale based on CECT evaluation. CEUS showed 22 hepatic injury sites in 16 animals and 17 splenic injury sites in other 14 animals. According to AAST scale, 2 grade I, 4 grade II, 3 grade III, 5 grade IV and 2 grade V hepatic lesions were present in 16 animals; 2 grade I, 4 grade II, 6 grade III and 2 grade IV splenic lesions in 14 animals. On CECT scan, 21 hepatic and 17 splenic injuries were demonstrated. According to Becker CT scaling for hepatic injury, 1 grade I, 2 grade II, 4 grade III, 5 grade IV and 2 grade V hepatic injuries were present. On the basis of Buntain spleen scaling, 2 grade I, 5 grade II, 5 grade III, 2 grade IV splenic injuries were showed. After Spearman rank correlation analysis, the agreement of CEUS with CECT on the degree of hepatic and splenic injury is 93.3% and 92.9%, respectively. CT is currently considered as the reference method for grading blunt abdominal trauma, according to experiment results, CEUS grading showed high levels of concordance with CECT. CEUS can accurately determine the degree of injury and will play an important role in clinical application.

CT of blunt hepatic trauma in children

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Nishiguchi, Hiroyasu; Shimizu, Toshihisa; Omura, Makoto; Nishio, Yoshinori; Watanabe, Shinsuke.

1991-01-01

CT findings of blunt hepatic trauma were studied in 27 children. Liver injury was classified into 3 types from mild to severe. Liver contusion was observed in 1, liver laceration in 21, and liver rupture in 5. Only 2 patients (7.4%) required surgery, and the others could be managed by conservative therapy. CT, which accurately reveals not only the severity of liver injury but also injuries of other abdominal organs and intraperitoneal bleeding, is important for the diagnosis of liver injury and determination of its treatment. (author)

DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

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Chen, Hanqing; Shen, Feng; Sherban, Alex; Nocon, Allison; Li, Yu; Wang, Hua; Xu, Ming-Jiang; Rui, Xianliang; Han, Jinyan; Jiang, Bingbing; Lee, Donghwan; Li, Na; Keyhani-Nejad, Farnaz; Fan, Jian-Gao; Liu, Feng; Kamat, Amrita; Musi, Nicolas; Guarente, Leonard; Pacher, Pal; Gao, Bin; Zang, Mengwei

2018-02-19

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. The dysregulation of SIRT1

Effect of iron, taurine and arginine on rat hepatic fibrosis

International Nuclear Information System (INIS)

Song Liangwen; Wang Dewen; Cui Xuemei

1997-01-01

Objective: The promotion role of iron on pathogenesis of hepatic fibrosis and the protective role of taurine and L-arginine against hepatic fibrosis were studied. Method: The model of rat radiation hepatic fibrosis was used. Experimental rats were divided into 0 Gy, 30 Gy, 30 Gy + iron, 30 Gy + taurine and 30 Gy + L-arginine groups. Serum iron, liver tissue hydroxyproline (Hyp) and malondialdehyde (MDA) were measured one and three months respectively after irradiation of hepatic tissue, production and distribution characteristics of hepatic tissue type I and III collagen were observed with a polarizing microscope. Results: Administration of iron agent could significantly increase hepatic tissue MDA content and serum iron concentration, one month after irradiation, hepatic tissue Hyp in 30 Gy + iron group began to increase, and collagen in hepatic tissue obviously increased. Taurine and L-arginine could reduce serum iron concentration and decrease production of hepatic fissure Hyp. Conclusion: Exogenous iron agent could promote early development of radiation hepatic fibrosis; taurine and arginine could diminish pathologic alteration of hepatic fibrosis to a certain extent

Effects of hepatic ischemia-reperfusion injury on the P-glycoprotein activity at the liver canalicular membrane and blood-brain barrier determined by in vivo administration of rhodamine 123 in rats.

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Miah, Mohammad K; Shaik, Imam H; Bickel, Ulrich; Mehvar, Reza

2014-04-01

To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood-brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker. Rats were subjected to 90 min of partial ischemia or sham surgery, followed by 12 or 24 h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis. P-gp protein levels at the liver canalicular membrane were increased by twofold after 24 h of reperfusion. However, the biliary excretion of RH-123 was reduced in these rats by 26%, presumably due to IR-induced reductions in the liver uptake of the marker and hepatic ATP concentrations. At the BBB, a 24% overexpression of P-gp in the 24-h IR animals was associated with a 30% decrease in the apparent brain uptake clearance of RH-123. The pharmacokinetics or brain distribution of RH-123 was not affected by the 12-h IR injury. Hepatic IR injury may alter the peripheral pharmacokinetics and brain distribution of drugs that are transported by P-gp and possibly other transporters.

Hepatic Complications of Anorexia Nervosa.

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Rosen, Elissa; Bakshi, Neeru; Watters, Ashlie; Rosen, Hugo R; Mehler, Philip S

2017-11-01

Anorexia nervosa (AN) has the highest mortality rate of all psychiatric illnesses due to the widespread organ dysfunction caused by the underlying severe malnutrition. Starvation causes hepatocyte injury and death leading to a rise in aminotransferases. Malnutrition-induced hepatitis is common among individuals with AN especially as body mass index decreases. Acute liver failure associated with coagulopathy and encephalopathy can rarely occur. Liver enzymes may also less commonly increase as part of the refeeding process due to hepatic steatosis and can be distinguished from starvation hepatitis by the finding of a fatty liver on ultrasonography. Individuals with AN and starvation-induced hepatitis are at increased risk of hypoglycemia due to depleted glycogen stores and impaired gluconeogenesis. Gastroenterology and hepatology consultations are often requested when patients with AN and signs of hepatitis are hospitalized. It should be noted that additional laboratory testing, imaging, or liver biopsy all have low diagnostic yield, are costly, and potentially invasive, therefore, not generally recommended for diagnostic purposes. While the hepatitis of AN can reach severe levels, a supervised increase in caloric intake and a return to a healthy body weight often quickly lead to normalization of elevated aminotransferases caused by starvation.

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

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Tobias Eggert

Full Text Available Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL, while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

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Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S.; Hollingsworth, John W.; Jiang, Dianhua; Lancaster, Lisa H.; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K.; Noble, Paul W.; Kimata, Koji; Schwartz, David A.

2008-01-01

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). PMID:18703791

Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

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Fu, Hailong; Chen, Huan; Wang, Chengcai; Xu, Haitao; Liu, Fang; Guo, Meng; Wang, Quanxing; Shi, Xueyin

2012-01-01

Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)–cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. PMID:22714712

Hepatocellular carcinoma with extensive hepatic artery injury: transcatheter arterial chemoembolization through collaterals after coil embolizatoin of gastric arteries

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Kim, Gab Choul; Yoon, Hyun Ki; Hwang, Jae Cheol; Lee, Duck Hee; Song, Ho Young; Suh, Dong Jin; Lee, Yung Sang; Chung, Young Hwa; Sung, Gyu Bo; Ko, Ki Young

1999-01-01

To evaluate the efficacy and safety of transcatheter arterial chemoembolization(TACE) after coil embolization of the gastroduodenal artery in hepatocellular carcinoma cases with multiple collateral arteries caused by proper hepatic artery injury. Between March 1997 and November 1998, a prospective trial of transcatheter arterial chemoembolization (TACE) was performed through collaterals from the gastroduodenal artery of 31 hepatocellular carcinoma patients with extensive proper hepatic artery injury due to repeated TACE. Among this number, 16 (group A) underwent TACE after coil embolization of the right gastric and gastroduodenal artery. The other 15 patients (group B) underwent TACE without coil embolization. The two groups had the same TNM stage and Clild-Pugh status. During the follow-up period, group A underwent additional TACE 3.3 times, and group B 2.8 times. The therapeutic effect of TACE was evaluated with computed tomography and by measuring alpha-fetoprotein levels. Complications were evaluated by means of gastrofibroscopy, laboratory data, and evaluation of the patients' clinical symptoms. The results obtained after six months and one year were compared within and between each group. At six months follow-up, CT findings had improved or were unchanged in 11 patients(69 %) in group A, and four patients(27 %) in group B(p = 0.032). In ten patients in each group, the level of alpha-fetoprotein was above 200 ng/ml. Its level was decreased in five patients(50 %) and three patients(30 %), respectively. The six-month survival rate was 81 % (13/16) in group A and 67% (10/15) in group B (p 0.43), while the one-year survival figures for these two groups were 50 % (8/16) and 20 % (3/15), respectively(p = 0.135). In group A, the CT findings were steady in five out of eight patients(63 %), while in groupB, CT findings showed that tumors with increased alpha-fetoprotein levels had increased in size and/or number. In group A, it was found that in two (33 %) of six

Hepatocellular carcinoma with extensive hepatic artery injury: transcatheter arterial chemoembolization through collaterals after coil embolizatoin of gastric arteries

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Kim, Gab Choul; Yoon, Hyun Ki; Hwang, Jae Cheol; Lee, Duck Hee; Song, Ho Young; Suh, Dong Jin; Lee, Yung Sang; Chung, Young Hwa; Sung, Gyu Bo [Ulsan Univ. College of Medicine, Seoul (Korea, Republic of); Ko, Ki Young [Catholic Univ. College of Medicine, Seoul (Korea, Republic of)

1999-09-01

To evaluate the efficacy and safety of transcatheter arterial chemoembolization(TACE) after coil embolization of the gastroduodenal artery in hepatocellular carcinoma cases with multiple collateral arteries caused by proper hepatic artery injury. Between March 1997 and November 1998, a prospective trial of transcatheter arterial chemoembolization (TACE) was performed through collaterals from the gastroduodenal artery of 31 hepatocellular carcinoma patients with extensive proper hepatic artery injury due to repeated TACE. Among this number, 16 (group A) underwent TACE after coil embolization of the right gastric and gastroduodenal artery. The other 15 patients (group B) underwent TACE without coil embolization. The two groups had the same TNM stage and Clild-Pugh status. During the follow-up period, group A underwent additional TACE 3.3 times, and group B 2.8 times. The therapeutic effect of TACE was evaluated with computed tomography and by measuring alpha-fetoprotein levels. Complications were evaluated by means of gastrofibroscopy, laboratory data, and evaluation of the patients' clinical symptoms. The results obtained after six months and one year were compared within and between each group. At six months follow-up, CT findings had improved or were unchanged in 11 patients(69 %) in group A, and four patients(27 %) in group B(p = 0.032). In ten patients in each group, the level of alpha-fetoprotein was above 200 ng/ml. Its level was decreased in five patients(50 %) and three patients(30 %), respectively. The six-month survival rate was 81 % (13/16) in group A and 67% (10/15) in group B (p 0.43), while the one-year survival figures for these two groups were 50 % (8/16) and 20 % (3/15), respectively(p = 0.135). In group A, the CT findings were steady in five out of eight patients(63 %), while in groupB, CT findings showed that tumors with increased alpha-fetoprotein levels had increased in size and/or number. In group A, it was found that in two (33 %) of six

Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.

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Sergio Duarte

Full Text Available Cyclooxygenase-2 (COX-2 is a mediator of hepatic ischemia and reperfusion injury (IRI. While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9 expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

Impaired TFEB-mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-induced Liver Injury and Steatosis in Mice.

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Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina; Li, Yuan; Williams, Jessica A; Li, Tiangang; Chavan, Hemantkumar; Krishnamurthy, Partha; He, Xi C; Li, Linheng; Ballabio, Andrea; Ni, Hong-Min; Ding, Wen-Xing

2018-05-18

Defects in lysosome function and autophagy contribute to pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes, evaluating the functions transcription factor EB (TFEB), which regulates lysosomal biogenesis. We performed studies with GFP-LC3 mice, mice with liver-specific deletion of transcription factor EB (TFEB), mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB, TFE3 double-knockout mice), and Tfeb flox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of chronic ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice were also given injections of torin1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time PCR to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB, compared with control mice, and hepatocytes had reduced lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting increased mTOR activation. Administration of torin1 increased liver levels of TFEB and reduced steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in liver developed less-severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared to mice carrying a control vector. Mice with knockdown of TFEB, as well as TFEB, TFE3 double-knockout mice, developed more severe liver injury in response to the

A comparison of hepatitis A and hepatitis B measures among vaccinated and susceptible online men who have sex with men.

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Gilbert, L K; Levandowski, B A; Scanlon, K E; Peterson, R S

2010-06-01

Hepatitis A virus (HAV) and hepatitis B virus (HBV) continue to be major health concerns among men who have sex with men (MSM). The Internet both facilitates high-risk sexual encounters and provides opportunities for promoting healthy behaviours. This study compared self-reported HAV and HBV vaccination levels, based on demographics, health characteristics, hepatitis knowledge, attitudes and risk behaviours among MSM using an online survey posted from February through June 2005. Each participant (n = 968) reported whether they were vaccinated, infected or susceptible for hepatitis A and/or for hepatitis B. Men whose health-care provider recommended vaccination were 12.91 (95% confidence interval [CI] 8.11, 20.55) times more likely to be vaccinated against HAV and 17.93 (95% CI 10.82, 29.70) times more likely to be vaccinated against HBV than those at risk of infection, respectively. These data provide essential information for public health professionals to successfully promote vaccination among members of this population.

Hepatic folate metabolism in the chronic alcoholic monkey

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Tamura, T.; Romero, J.J.; Watson, J.E.; Gong, E.J.; Halsted, C.H.

1981-01-01

To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of 3 H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected

CXC-chemokine regulation and neutrophil trafficking in hepatic ischemia-reperfusion injury in P-selectin/ICAM-1 deficient mice

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Crockett Elahé T

2007-05-01

Full Text Available Abstract Background Neutrophil adhesion and migration are critical in hepatic ischemia and reperfusion injury (I/R. P-selectin and the intercellular adhesion molecule (ICAM-1 can mediate neutrophil-endothelial cell interactions, neutrophil migration, and the interactions of neutrophils with hepatocytes in the liver. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy in reperfusion injury, indicating that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the aim of this study was to assess the role of P-selectin and ICAM-1 in neutrophil infiltration and liver injury during early and late phases of liver I/R. Methods Adult male wild-type and P-selectin/ICAM-1-deficient (P/I null mice underwent 90 minutes of partial liver ischemia followed by various periods of reperfusion (6, 15 h, and a survival study. Liver injury was assessed by plasma level of alanine aminotransferase (ALT and histopathology. The plasma cytokines, TNF-α, IL-6, MIP-2 and KC, were measured by ELISA. Results Reperfusion caused significant hepatocellular injury in both wild-type and P/I null mice as was determined by plasma ALT levels and liver histopathology. The injury was associated with a marked neutrophil infiltration into the ischemic livers of both wild-type and P/I null mice. Although the levels of ALT and neutrophil infiltration were slightly lower in the P/I null mice compared with the wild-type mice the differences were not statistically significant. The plasma cytokine data of TNF-α and IL-6 followed a similar pattern to ALT data, and no significant difference was found between the wild-type and P/I null groups. In contrast, a significant difference in KC and MIP-2 chemokine levels was observed between the wild-type and P/I null mice. Additionally, the survival study showed a trend towards increased survival in the P/I null group. Conclusion While ICAM-1 and P

Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

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Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

2016-06-01

Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice.

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Duwaerts, Caroline C; Amin, Amin M; Siao, Kevin; Her, Chris; Fitch, Mark; Beysen, Carine; Turner, Scott M; Goodsell, Amanda; Baron, Jody L; Grenert, James P; Cho, Soo-Jin; Maher, Jacquelyn J

2017-09-01

The factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets. Mice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping. Mice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate-fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat. The macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity.

Developing theoretically based and culturally appropriate interventions to promote hepatitis B testing in 4 Asian American populations, 2006-2011.

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Maxwell, Annette E; Bastani, Roshan; Glenn, Beth A; Taylor, Victoria M; Nguyen, Tung T; Stewart, Susan L; Burke, Nancy J; Chen, Moon S

2014-05-01

Hepatitis B infection is 5 to 12 times more common among Asian Americans than in the general US population and is the leading cause of liver disease and liver cancer among Asians. The purpose of this article is to describe the step-by-step approach that we followed in community-based participatory research projects in 4 Asian American groups, conducted from 2006 through 2011 in California and Washington state to develop theoretically based and culturally appropriate interventions to promote hepatitis B testing. We provide examples to illustrate how intervention messages addressing identical theoretical constructs of the Health Behavior Framework were modified to be culturally appropriate for each community. Intervention approaches included mass media in the Vietnamese community, small-group educational sessions at churches in the Korean community, and home visits by lay health workers in the Hmong and Cambodian communities. Use of the Health Behavior Framework allowed a systematic approach to intervention development across populations, resulting in 4 different culturally appropriate interventions that addressed the same set of theoretical constructs. The development of theory-based health promotion interventions for different populations will advance our understanding of which constructs are critical to modify specific health behaviors.

New Insights Into the Relationships Among Alcohol Consumption, Hepatocellular Carcinoma and Hepatitis C Virus Infection

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Sabouri Ghannad

2014-04-01

Full Text Available Context Viral hepatitis and the consumption of alcohol are recognized as important reasons for the development of liver disease throughout the world. It would also seem that chronic alcoholism causes more severe and rapid progression of liver disease in patients with chronic hepatitis C, leading to more frequent liver cirrhosis and hepatocellular carcinoma. Evidence Acquisition The data for this article were obtained through an initial Medline search and from the references of relevant articles, and used to provide updated information on the relationship between alcohol consumption and the hepatitis C virus. Results Excessive alcohol consumption among patients with chronic hepatitis C is likely to result in more severe hepatic injuries, promote pathologic progression to cirrhosis, and increase the risk of developing hepatocellular carcinoma. Although the exact mechanisms involved in the progression of chronic hepatitis C in alcoholic patients have not been definitely established, possible alcohol-induced enhancement of viral replication, iron overload, immunologic suppression, the role of NF-kappa B, and the signaling pathways involved in its activation, have been suggested. Significant correlations have been reported between hepatitis C virus RNA levels and the amount of alcohol consumed by an individual. Interferon therapy is less effective for alcohol patients, than non-alcoholic patients, even after a period of abstinence. The obtained data suggest that a hepatitis C virus infection is an important cofactor in the pathogenesis of liver disease among patients with an alcohol problem. Conclusions In light of a possible synergistic effect between alcohol and hepatitis C virus replication, total abstention ought to be recommended, and due to alcohol's inhibitory effect on interferon therapy, patients with alcohol problems should not be treated until they stop drinking.

Curcumin promotes nerve regeneration and functional recovery after sciatic nerve crush injury in diabetic rats.

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Ma, Junxiong; Yu, Hailong; Liu, Jun; Chen, Yu; Wang, Qi; Xiang, Liangbi

2016-01-01

Curcumin is capable of promoting peripheral nerve regeneration in normal condition. However, it is unclear whether its beneficial effect on nerve regeneration still exists under diabetic mellitus. The present study was designed to investigate such a possibility. Diabetes in rats was developed by a single dose of streptozotocin at 50 mg/kg. Immediately after nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with curcumin (50 mg/kg, 100 mg/kg and 300 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. Axonal regeneration and functional recovery was significantly enhanced by curcumin, which were significantly better than those in vehicle saline group. In addition, high doses of curcumin (100 mg/kg and 300 mg/kg) achieved better axonal regeneration and functional recovery than low dose (50 mg/kg). In conclusion, curcumin is capable of promoting nerve regeneration after sciatic nerve crush injury in diabetes mellitus, highlighting its therapeutic values as a neuroprotective agent for peripheral nerve injury repair in diabetes mellitus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury

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Kosuke Fujita

2017-06-01

Full Text Available Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter-driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

Interventions to reduce needle stick injuries at a tertiary care centre

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Mehta A

2010-01-01

Full Text Available Background: Occupational exposure to blood/body fluids is associated with risk of infection with blood borne pathogens like human immunodeficiency virus (HIV, hepatitis B virus (HBV and hepatitis C virus (HCV. Materials and Methods: We carefully document needle stick injuries (NSI and implement post-exposure prophylaxis (PEP. We report a four-year continuing surveillance study where 342 healthcare workers (HCWs sustained NSI. PEP was given to HCWs injured from seropositive sources. If the source was HbsAg positive, HCWs were given a hepatitis B immunization booster. If the HCW was antiHBs negative, both hepatitis B immunoglobulin (HBIG and hepatitis B vaccine were administered. For HCWs who sustained injuries from HIV positive sources, antiretroviral therapy was started. Follow-up was done after three and six months of exposure. Recent interventions by the infection control committee at our hospital reduced NSI considerably during intravenous line administration and glucose monitoring. Results and Discussion: Of 342 injuries, 254 were from known sources and 88 from unknown sources. From known sources, 37 were seropositive; 13 for HIV, 15 for HCV, nine for HBV. Sixty six sharp injuries were sustained through garbage bags, 43 during IV line administration, 41 during injection administration, 35 during needle recapping, 32 during blood collection, 27 during blood glucose monitoring, 24 from OT instruments, 17 during needle disposal, 16 while using surgical blade, 7 during suturing and 34 from miscellaneous sources. Conclusion: No case of seroconversion has taken place, so far, as a result of needle stick injuries at our centre.

Statin-induced liver injury in an area endemic for hepatitis B virus infection: risk factors and outcome analysis.

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Wang, Li Yueh; Huang, Yi-Shin; Perng, Chin-Lin; Huang, Bryan; Lin, Han-Chieh

2016-09-01

Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the seven available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the two independent risk factors of SILI (OR and 95% CI: 1.93, 1.08-3.35, P = 0.025, and 1.73, 1.07-2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after rechallenge of other statins. High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study. © 2016 The British Pharmacological Society.

Ginsenoside 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

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Han, Xin; Song, Jian; Lian, Li-Hua; Yao, You-Li; Shao, Dan-Yang; Fan, Ying; Hou, Li-Shuang; Wang, Ge; Zheng, Shuang; Wu, Yan-Ling; Nan, Ji-Xing

2018-06-22

Ginseng is widely used in energy drinks, dietary supplements and herbal medicines, and its pharmacological actions are related with energy metabolism. As an important modulating energy metabolism pathway, liver X receptors (LXRs) can promote the resolving of hepatic fibrosis and inflammation. The present study aims to evaluate the regulation of 25-OCH3-PPD, a ginsenoside isolated from Panax ginseng, against hepatic fibrosis and inflammation in thioacetamide (TAA)-stimulated mice by activating LXRs pathway. 25-OCH3-PPD decreases serum ALT/AST levels and improves the histological pathology of liver in TAA-induced mice; attenuates transcripts of pro-fibrogenic markers associated with hepatic stellate cell activation; attenuates the levels of pro-Inflammatory cytokines and blocks apoptosis happened in liver; inhibits NLRP3 inflammasome by affecting P2X7R activation; regulates PI3K/Akt and LKB1/AMPK-SIRT1. 25-OCH3-PPD also facilitates LX25Rs and FXR activities decreased by TAA stimulation. 25-OCH3-PPD also decreases α-SMA via regulation of LXRs and P2X7R-NLRP3 in vitro. Our data suggest the possibility that 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

The impact of a massive transfusion protocol (1:1:1) on major hepatic injuries: does it increase abdominal wall closure rates?

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Ball, Chad G; Dente, Christopher J; Shaz, Beth; Wyrzykowski, Amy D; Nicholas, Jeffrey M; Kirkpatrick, Andrew W; Feliciano, David V

2013-10-01

Massive transfusion protocols (MTPs) using high plasma and platelet ratios for exsanguinating trauma patients are increasingly popular. Major liver injuries often require massive resuscitations and immediate hemorrhage control. Current published literature describes outcomes among patients with mixed patterns of injury. We sought to identify the effects of an MTP on patients with major liver trauma. Patients with grade 3, 4 or 5 liver injuries who required a massive blood component transfusion were analyzed. We compared patients with high plasma:red blood cell:platelet ratio (1:1:1) transfusions (2007-2009) with patients injured before the creation of an institutional MTP (2005-2007). Among 60 patients with major hepatic injuries, 35 (58%) underwent resuscitation after the implementation of an MTP. Patient and injury characteristics were similar between cohorts. Implementation of the MTP significantly improved plasma: red blood cell:platelet ratios and decreased crystalloid fluid resuscitation (p = 0.026). Rapid improvement in early acidosis and coagulopathy was superior with an MTP (p = 0.009). More patients in the MTP group also underwent primary abdominal fascial closure during their hospital stay (p = 0.021). This was most evident with grade 4 injuries (89% vs. 14%). The mean time to fascial closure was 4.2 days. The overall survival rate for all major liver injuries was not affected by an MTP (p = 0.61). The implementation of a formal MTP using high plasma and platelet ratios resulted in a substantial increase in abdominal wall approximation. This occurred concurrently to a decrease in the delivered volume of crystalloid fluid.

Athlete’s Hepatitis in a Young Healthy Marathon Runner

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Hafiz Khan

2018-04-01

Full Text Available Athlete’s hepatitis is an uncommon clinical condition characterized by a significant ischemic insult to the liver. The most likely pathogenesis is decreased blood supply to the liver resulting in significant hypoxic hepatocyte injury. We report a case of a 48-year-old healthy young male who presented with athlete’s hepatitis confirmed by liver biopsy after a 14-mile marathon run. To our knowledge, this is the second case of athlete’s ischemic hepatitis reported in the literature. It is a diagnosis worth considering in patients involved in extreme exercise programs.

Antioxidant effects of Spirulina supplement against lead acetate-induced hepatic injury in rats

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Walid Hamdy El-Tantawy

2016-10-01

Full Text Available Lead is a toxic metal that induces a wide range of behavioral, biochemical and physiological effects in humans. Oxidative damage has been proposed as a possible mechanism involved in lead toxicity. The current study was carried out to evaluate the antioxidant activities of Spirulina supplement against lead acetate -induced hepatic injury in rats. Five groups of rats were used in this study, Control, Lead acetate (100 mg/kg, Lead acetate (100 mg/kg + 0.5 g/kg Spirulina, Lead acetate (100 mg/kg + 1 g/kg Spirulina and Lead acetate + 25 mg/100 g Vitamin C (reference drug. All experimental groups received the oral treatment by stomach tube once daily for 4 weeks. Lead intoxication resulted in a significant increase in serum alanine transaminae (ALT, aspartate transaminae (AST activities, liver homogenate tumor necrosis factor-α (TNF-α, caspase-3, malondialdehyde (MDA, nitric oxide (NO levels and a significant decline of total serum protein, liver homogenate reduced glutathione (GSH level and superoxide dismutase (SOD activity. Both doses of Spirulina supplement as well as Vitamin C succeeded to improve the biochemical parameters of serum and liver and prevented the lead acetate-induced significant changes on plasma and antioxidant status of the liver. Both doses of Spirulina supplement had the same anti-apoptotic activity and high dose exhibited more antioxidant activity than that of low dose. In conclusion, the results of the present work revealed that Spirulina supplement had protective, antioxidant and anti-apoptotic effects on lead acetate-induced hepatic damage.

Chronic hepatitis C and fibrosis: evidences for possible estrogen benefits

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Liana Codes

Full Text Available The main injury caused by hepatitis C virus is the hepatic fibrosis, as a result of a chronic inflammatory process in the liver characterized by the deposit of components from the extracellular matrix. The fibrosis development leads to the modification of the hepatic architecture, of the hepatocellular function and to irregularities in the microcirculation. The tissue remodeling process observed in fibrosis has stellate cells, located at the space of Disse, as main acting agents. These cells, in response to a harmful stimulus, undergo phenotypic changes from non-proliferating cells to proliferating cells that express a- smooth-muscle actin (a-SMA, a process called as transdifferentiation. There are evidences that the oxidative stress is involved in the chronic liver disease and serves as bond between the injury and the hepatic fibrosis. A number of studies suggest that the estrogen, at physiological levels, presents an antifibrogenic action probably through an antioxidant effect, decreasing the levels of lipid peroxidation products in the liver and blood, thus inhibiting the myofibroblastic transformation of stellate cells and contributing for gender-associated differences in relation to the fibrosis development. The aim of this paper was to describe data from literature concerning the interaction between chronic hepatitis C and estrogens, pregnancy, use of oral contraceptives, menopause and hormone reposition therapy.

Caregivers' support needs and factors promoting resiliency after brain injury.

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Kitter, Bryony; Sharman, Rachael

2015-01-01

This article explores the challenges, support needs and coping strategies of caregivers of people with an acquired brain injury (ABI). Semi-structured interviews were conducted with caregivers (n = 20) to explore their support services received, access barriers, utility of services, needed supports, coping strategies and factors promoting life satisfaction. The team recorded, transcribed verbatim and inductively analysed all interviews. Through thematic data analysis, three central themes were revealed: (a) barriers impeding quality-of-life, (b) support needed to improve quality-of-life and (c) factors enabling quality-of-life. All perspectives from the participants involved are synthesized to provide a rich depiction of caregivers' support needs and coping strategies. Two specific findings of interest include a negative association between severity of brain injury and caregiver's desire to direct treatment, as well as a distinct service gap in assistance for caregivers who are caring for someone with violent/offending behaviours. This study recommends short- and long-term changes, given Australia's upcoming National Disability Insurance Scheme, to increase caregiver quality-of-life, which will ultimately affect the rehabilitation outcomes of persons with ABI.

TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.

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Wang, Jing; Qiao, Luhua; Hou, Zhouhua; Luo, Guangxiang

2017-01-15

Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope. TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1

Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression

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Juan Du

2018-04-01

Full Text Available Andrographolide (ANDRO has been studied for its immunomodulation, anti-inflammatory, and neuroprotection effects. Because brain hypoxia is the most common factor of secondary brain injury after traumatic brain injury, we studied the role and possible mechanism of ANDRO in this process using hypoxia-injured astrocytes. Mouse cortical astrocytes C8-D1A (astrocyte type I clone from C57/BL6 strains were subjected to 3 and 21% of O2 for various times (0–12 h to establish an astrocyte hypoxia injury model in vitro. After hypoxia and ANDRO administration, the changes in cell viability and apoptosis were assessed using CCK-8 and flow cytometry. Expression changes in apoptosis-related proteins, autophagy-related proteins, main factors of JNK pathway, ATG5, and S100B were determined by western blot. Hypoxia remarkably damaged C8-D1A cells evidenced by reduction of cell viability and induction of apoptosis. Hypoxia also induced autophagy and overproduction of S100B. ANDRO reduced cell apoptosis and promoted cell autophagy and S100B expression. After ANDRO administration, autophagy-related proteins, S-100B, JNK pathway proteins, and ATG5 were all upregulated, while autophagy-related proteins and s100b were downregulated when the jnk pathway was inhibited or ATG5 was knocked down. ANDRO conferred a survival advantage to hypoxia-injured astrocytes by reducing cell apoptosis and promoting autophagy and s100b expression. Furthermore, the promotion of autophagy and s100b expression by ANDRO was via activation of jnk pathway and regulation of ATG5.

Circulating Extracellular Histones Are Clinically Relevant Mediators of Multiple Organ Injury.

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Kawai, Chihiro; Kotani, Hirokazu; Miyao, Masashi; Ishida, Tokiko; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

2016-04-01

Extracellular histones are a damage-associated molecular pattern (DAMP) involved in the pathogenesis of various diseases. The mechanisms of histone-mediated injury in certain organs have been extensively studied, but an understanding of the pathophysiological role of histone-mediated injury in multiple organ injury remains elusive. To elucidate this role, we systemically subjected C57BL/6 mice to various doses of histones and performed a chronological evaluation of the morphological and functional changes in the lungs, liver, and kidneys. Notably, histone administration ultimately led to death after a dose-dependent aggravation of multiple organ injury. In chronological studies, pulmonary and hepatic injuries occurred within 15 minutes, whereas renal injuries presented at a later phase, suggesting that susceptibility to extracellular histones varies among organs. Histones bound to pulmonary and hepatic endothelial cells immediately after administration, leading to endothelial damage, which could be ameliorated by pretreatment with heparin. Furthermore, release of another DAMP, high-mobility group protein box 1, followed the histone-induced tissue damage, and an antibody against the molecule ameliorated hepatic and renal failure in a late phase. These findings indicate that extracellular histones induce multiple organ injury in two progressive stages-direct injury to endothelial cells and the subsequent release of other DAMPs-and that combination therapies against extracellular histones and high-mobility group protein box 1 may be a promising strategy for treating multiple organ injury. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Effects of defibrotide, a novel oligodeoxyribonucleotide, on ischaemia and reperfusion injury of the rat liver.

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Kim, Kwang Joon; Shin, Yong Kyoo; Song, Jin Ho; Oh, Byung Kwon; Choi, Myung Sup; Sohn, Uy Dong

2002-02-01

1. The purpose of this study was to investigate the protective effects of defibrotide, a single-stranded polydeoxyribonucleotide, on ischaemia-reperfusion injury to the liver using a rat model. 2. Ischaemia of the left and median lobes was created by total inflow occlusion for 30 min followed by 60 min of reperfusion. Hepatic injury was assessed by the release of liver enzymes (alanine transferase, ALT and lactic dehydrogenase, LDH). Hepatic oxidant stress was measured by superoxide production, lipid peroxidation and nitrite/nitrate formation. Leukocyte-endothelium interaction and Kupffer cell mobilization were quantified by measuring hepatic myeloperoxidase (MPO), polymorphonuclear leukocyte adherence to superior mesenteric artery (SMA) and immunostaining of Kupffer cell. 3. Defibrotide treatment resulted in a significant inhibition of postreperfusion superoxide generation, lipid peroxidation, serum ALT activity, serum LDH activity, MPO activity, serum nitrite/nitrate level, leukocyte adherence to SMA, and Kupffer cell mobilization, indicating a significant attenuation of hepatic dysfunction. 4. A significant correlation existed between liver ischaemia/reperfusion and hepatic injury, suggesting that liver ischaemia/reperfusion injury is mediated predominantly by generation of oxygen free radicals and mobilization of Kupffer cells. 5. We conclude that defibrotide significantly protects the liver against liver ischaemia/reperfusion injury by interfering with Kupffer cell mobilization and formation of oxygen free radicals. This study provides strong evidence that defibrotide has important beneficial effects on acute inflammatory tissue injury such as that occurring in the reperfusion of the ischaemic liver.

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

International Nuclear Information System (INIS)

Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J.

2014-01-01

The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na + -K + -ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na + -K + -ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na + -K + -ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis

Exosomes from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway.

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Du, Yingdong; Li, Dawei; Han, Conghui; Wu, Haoyu; Xu, Longmei; Zhang, Ming; Zhang, Jianjun; Chen, Xiaosong

2017-01-01

directly fuse with target hepatocytes or HL7702 cells and increase the activity of sphingosine kinase and synthesis of sphingosine-1-phosphate (S1P). Furthermore, the inhibition of SK1 or S1P1 receptor completely abolished the protective and proliferative effects of hiPSC-MSCs-Exo on hepatocytes, both in vitro and in vivo. Our results demonstrated that hiPSC-MSCs-Exo could alleviate hepatic I/R injury via activating sphingosine kinase and sphingosine-1-phosphate pathway in hepatocytes and promote cell proliferation. These findings represent a novel mechanism that potentially contributes to liver regeneration and have important implications for new therapeutic approaches to acute liver disease. © 2017 The Author(s). Published by S. Karger AG, Basel.

Left hepatic vein injury during laparoscopic antireflux surgery for large para-oesophageal hiatus hernia

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Nagpal Anish

2009-01-01

Full Text Available Although the advent of laparoscopic fundoplication has increased both patient and physician acceptance of antireflux surgery, it has become apparent that the laparoscopic approach is associated with an increased risk of some complications and as well as the occurrence of new complications specific to this approach. One such complication occurred in our patient who had intra-operative left hepatic vein injury during laparoscopic floppy Nissen fundoplication for large para-oesophageal rolling hernia. With timely conversion to open procedure, the bleeding was controlled and the antireflux and the procedure were completed uneventfully. However, this suggests that even with an experience in advanced laparoscopy surgery, complications can occur. Clear understanding of the normal and pathologic anatomy and its variations facilitates laparoscopic surgery and should help the surgeon avoid complications. The incidence of some of these complications decreases as surgeons gain experience; however, new complications can arise due to the increase in such procedures.

Role of berberine in ameliorating Schistosoma mansoni-induced hepatic injury in mice

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Mohamed A Dkhi

2014-01-01

Full Text Available BACKGROUND: Schistosomiasis is caused by helminth parasites of the genus Schistosoma. Berberine chloride (BER, an isoquinoline alkaloid, has been used in vivo for its antiparasitic, antioxidant and hepatoprotective properties. In this study, the protective effect of BER and praziquantel has been compared for the extent of schistosomiasis-induced oxidative stress in hepatic tissue of mice. RESULTS: S. mansoni was able to induce inflammation and injury to the liver, evidenced (i by an increase in inflammatory cellular infiltrations, dilated sinusoids and vacuolated hepatocytes, (ii by decreased levels of alanine and aspartate aminotransferases and increased levels of alkaline phosphatase, γ-glutamyl transferase in the liver homogenate, (iii by increased production of nitric oxide and thiobarbituric acid reactive substances, and (iv by lowered glutathione levels and decreased activities of catalase and superoxide dismutase, respectively. All these infection-induced parameters were significantly altered during BER treatment. In particular, berberine counteracted the S. mansoni-induced loss of glutathione and the activities of catalase and superoxide dismutase. CONCLUSION: Based on these results, it is concluded that berberine could ameliorate pre-existing liver damage and oxidative stress conditions due to schistosomiasis.

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

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Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

Needle stick injury in a radiology department: a decade analysis

International Nuclear Information System (INIS)

Sayani, R.; Rajani, A.

2012-01-01

Objectives: To determine the frequency of needle stick injury in health care workers of radiology department. Study type, settings and duration: Cross sectional, observational study conducted at the Radiology department of Aga Khan University hospital from January 2000 to May 2010. Subject and Methods: All self-reported needle stick injuries data of Health care workers of radiology department was recorded. The personnel involved (Radiologist, resident, radiographer, nurses etc), area of working and the causes of injury were identified including the procedural or post procedural details. Patient's status of hepatitis or blood borne infection was also noted. Data was recorded and analyzed in Excel worksheet. Results: A total of 55 health workers reported needle stick injuries at all sections of radiology departments with maximum number needle stick injuries at general radiography, fluoroscopy and IVP section. Radiographers and radiology residents received the maximum number of injuries. Major cause of injury was cannulation however, many injuries occurred during disposing or handling of bin. In majority of cases the patients were not infected with any known blood borne infections. Conclusions: Doctors and nurses get needle-stick injuries while carrying out clinical procedures, while, ancillary staff get infected post procedure during disposal of garbage. Policy message: Good occupational health and safety practices must be promoted to all staff. Safer disposal of needles is an important area where practice and procedure needs to be carefully reviewed. It is necessary to undertake a risk assessment, to offer counseling and Post Exposure Prophylaxis and treatment where necessary. (author)

Radiographic evaluation of hepatic trauma

International Nuclear Information System (INIS)

Federle, M.P.

1985-01-01

The incidence of significant abdominal trauma continues to rise and accounts currently for approximately 10 percent of the annual 130,000 trauma-related deaths in the United States. Over 60 percent of patients are from 10 to 40 years of age, with a striking predominance of males. Children are mostly victims of blunt trauma, while some large reviews of liver trauma in adults show a prevalence of penetrating injuries. Injury to the liver is second only to the spleen in incidence of intraperitoneal injuries. Morbidity and mortality from hepatic trauma are related to the mechanism and extent of injury. Penetrating injuries generally have a lower mortality, about 5 percent, especially if they are due to stab wounds or low velocity gunshot wounds. Shotgun and high velocity gunshot wounds may cause massive fragmentation of the liver and are associated with proportionately greater mortality. The mortality from blunt trauma is from 15 to 45 percent in many large series. Death from isolated liver injury is uncommon, but is usually due to uncontrolled hemorrhage. Injury to other abdominal organs is associated in many cases, as are injuries to the head, chest, and limbs. The extraabdominal injuries are frequently more apparent clinically, but may mask potentially life-threatening abdominal visceral injuries

A rat model of concurrent combined injuries (polytrauma)

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Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A; Schwacha, Martin G; Messina, Joseph L

2015-01-01

Polytrauma, a combination of injuries to more than one body part or organ system, is common in modern warfare and in automobile and industrial accidents. The combination of injuries can include burn injury, fracture, hemorrhage, trauma to the extremities, and trauma to specific organ systems. To investigate the effects of combined injuries, we have developed a new and highly reproducible model of polytrauma. This model combines burn injury with soft tissue and gastrointestinal (GI) tract trauma. Male Sprague Dawley rats were subjected to a 15-20% total body surface area scald burn, or a single puncture of the cecum with a G30 needle, or the combination of both injuries (polytrauma). Unlike many ‘double hit’ models, the injuries in our model were performed simultaneously. We asked whether multiple minor injuries, when combined, would result in a distinct phenotype, different from single minor injuries or a more severe single injury. There were differences between the single injuries and polytrauma in the maintenance of blood glucose, body temperature, body weight, hepatic mRNA and circulating levels of TNF-α, IL-1β and IL-6, and hepatic ER-stress. It has been suggested that models utilizing combinatorial injuries may be needed to more accurately model the human condition. We believe our model is ideal for studying the complex sequelae of polytrauma, which differs from single injuries. Insights gained from this model may suggest better treatment options to improve patient outcomes. PMID:26884923

[Therapeutic effects on cerebral white matter injury of premature infants treated with acupuncture for promoting the governor vessel and tranquilizing the mind].

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Cai, Shuying; Liu, Zhenhuan; Peng, Guilan; Huang, Xinfa; Li, Yinlan; Hu, Shuxiang

2018-01-12

To explore the repair effects of acupuncture for promoting the governor vessel and tranquilizing the mind (acupuncture technique) on cerebral white matter injury of premature infants. A total of 56 cases of cerebral whiter matter injury of premature infants, the fetal age less than 35 weeks were selected and randomized into an observation group (27 cases) and a control group (29 cases). The routine basic rehabilitation therapy was used in the two groups. Additionally, in the observation group, the acupuncture technique was added, once a day and the treatment for 15 days was as 1 course. Totally, 3 courses of treatment were required. Before and after treatment, the cranial magnetic resonance imaging (MRI) and the diffusion tensor imaging (DTI) were adopted to observe the location and severity of cerebral white matter injury. The Gesell developmental scale was used to assess the nerve motor development. After treatment, the difference was not significant statistically in the severity of cerebral white matter injury in the infants between the two groups ( P >0.05). The FA value of cerebral white matter in the interesting zone was increased as compared with that before treatment in the infants of the two groups (both P control groups ( P control group (all P 0.05). Acupuncture technique for promoting the governor vessel and tranquilizing the mind promotes the repair of the function in the premature infants with cerebral white matter injury and further benefits the promotion of the intelligence.

Predictors of hepatitis A vaccine coverage among university students in Korea.

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Park, Seungmi; Choi, Jeong Sil

2016-01-01

To investigate the status of hepatitis A vaccination, knowledge, and health beliefs among university students in Korea and identify factors influencing their hepatitis A vaccination rate. A self-reporting survey was conducted with 367 university students in Korea via descriptive survey. Data were collected on demographics, status of hepatitis A vaccination, knowledge, and health beliefs. The hepatitis A vaccination rate was 23.4%. The hepatitis A vaccination rate was significantly higher in those who had a general awareness about the hepatitis A (odds ratio [OR] = 3.56, P = 0.003), those with some overseas travel experience (OR = 2.64, P = 0.025), those perceiving the benefits of hepatitis A vaccination (OR = 1.66, P = 0.023), and those perceiving barriers (inversed) to hepatitis A vaccination (OR = 1.95, P = 0.011). To promote hepatitis A vaccination among university students, information and education should be provided to improve their health beliefs. In addition, this demographic should be a major target population for hepatitis A vaccination. This study's results suggest that the development of national promotional campaigns and hepatitis A vaccination programs based on predictors of the vaccination rate are needed. © 2015 Japan Academy of Nursing Science.

Endoscopic Management of Perforation of Right Hepatic Duct Following Non-Surgical Abdominal Trauma

OpenAIRE

Sharma, B. C.; Maini, A.; Saraswat, V. A.

1997-01-01

Isolated bile duct injuries after blunt abdominal trauma are rare. Surgery is the usual mode of treatment. We report a patient with a right hepatic duct injury following blunt abdominal trauma who was managed successfully by endoscopic papillotomy.

Yin Yang 1 Promotes Hepatic Gluconeogenesis Through Upregulation of Glucocorticoid Receptor

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Lu, Yan; Xiong, Xuelian; Wang, Xiaolin; Zhang, Zhijian; Li, Jin; Shi, Guojun; Yang, Jian; Zhang, Huijie; Ning, Guang; Li, Xiaoying

2013-01-01

Gluconeogenesis is critical in maintaining blood glucose levels in a normal range during fasting. In this study, we investigated the role of Yin Yang 1 (YY1), a key transcription factor involved in cell proliferation and differentiation, in the regulation of hepatic gluconeogenesis. Our data showed that hepatic YY1 expression levels were induced in mice during fasting conditions and in a state of insulin resistance. Overexpression of YY1 in livers augmented gluconeogenesis, raising fasting blood glucose levels in C57BL/6 mice, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated hyperglycemia in wild-type and diabetic db/db mice. At the molecular level, we further demonstrated that the major mechanism of YY1 in the regulation of hepatic glucose production is to modulate the expression of glucocorticoid receptor. Therefore, our study uncovered for the first time that YY1 participates in the regulation of hepatic gluconeogenesis, which implies that YY1 might serve as a potential therapeutic target for hyperglycemia in diabetes. PMID:23193188

[Hepatitis C in women planning a pregnancy: current opinions].

Science.gov (United States)

Langlet, P; Lasser, L; Sidi, B

2005-01-01

Chronic hepatitis C (VHC) is a worldwide public health issue. The mother-to-child transmission could be the main cause of hepatitis C infection in children. Despite the risk of histological injuries, chronic hepatitis C is not a contra-indication to pregnancy. In patients with VHC, there is no evidence that the outcome could be modified. In co-infected patients (VIH-VHC), a caesarean should be proposed taking into account the significant risk of mother-to-child transmission. Breast-feeding is not contra-indicated. Systematic screening of VHC, discussed in this article, could be proposed in woman planning a pregnancy.

Systemic Lidocaine Does Not Attenuate Hepatic Dysfunction After Liver Surgery in Rats

NARCIS (Netherlands)

de Graaf, Wilmar; Diepenhorst, Gwen M. P.; Herroeder, Susanne; Erdogan, Deha; Hollmann, Markus W.; van Gulik, Thomas M.

2012-01-01

BACKGROUND: Lidocaine has been shown to attenuate ischemia-reperfusion (I/R) injury in the heart, lung, and brain, potentially due to modulation of inflammatory responses and apoptotic signaling pathways. Because hepatic I/R injury after liver surgery still poses a significant risk for postoperative

Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.

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Gotoh, Saki; Negishi, Masahiko

2015-09-22

Statin therapy is known to increase blood glucose levels in humans. Statins utilize pregnane X receptor (PXR) and serum/glucocorticoid regulated kinase 2 (SGK2) to activate phosphoenolpyruvate carboxykinase 1 (PEPCK1) and glucose-6-phosphatase (G6Pase) genes, thereby increasing glucose production in human liver cells. Here, the novel statin/PXR/SGK2-mediated signaling pathway has now been characterized for hepatic gluconeogenesis. Statin-activated PXR scaffolds the protein phosphatase 2C (PP2C) and SGK2 to stimulate PP2C to dephosphorylate SGK2 at threonine 193. Non-phosphorylated SGK2 co-activates PXR-mediated trans-activation of promoters of gluconeogenic genes in human liver cells, thereby enhancing gluconeogenesis. This gluconeogenic statin-PXR-SGK2 signal is not present in mice, in which statin treatment suppresses hepatic gluconeogenesis. These findings provide the basis for statin-associated side effects such as an increased risk for Type 2 diabetes.

Risk factors for central bile duct injury complicating partial liver resection

NARCIS (Netherlands)

Boonstra, E. A.; de Boer, M. T.; Sieders, E.; Peeters, P. M. J. G.; de Jong, K. P.; Slooff, M. J. H.; Porte, R. J.

Background: Bile duct injury is a serious complication following liver resection. Few studies have differentiated between leakage from small peripheral bile ducts and central bile duct injury (CBDI), defined as an injury leading to leakage or stenosis of the common bile duct, common hepatic duct,

Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells

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Otani, Satoshi [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Kakinuma, Sei, E-mail: skakinuma.gast@tmd.ac.jp [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Kamiya, Akihide [Institute of Innovative Science and Technology, Tokai University, Isehara (Japan); Goto, Fumio; Kaneko, Shun; Miyoshi, Masato; Tsunoda, Tomoyuki; Asano, Yu; Kawai-Kitahata, Fukiko; Nitta, Sayuri; Nakata, Toru; Okamoto, Ryuichi; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Asahina, Yasuhiro [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Yamaguchi, Tomoyuki [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Koshikawa, Naohiko [Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Seiki, Motoharu [Medical School, Kanazawa University, Kanazawa (Japan); Nakauchi, Hiromitsu [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); and others

2016-01-22

Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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Z.G. Zhao

2014-02-01

Full Text Available The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL on lipopolysaccharide (LPS-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1, myeloperoxidase (MPO, and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

Energy Technology Data Exchange (ETDEWEB)

Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J. [Institute of Microcirculation, Hebei North University, Zhangjiakou, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

2014-02-17

The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na{sup +}-K{sup +}-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na{sup +}-K{sup +}-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na{sup +}-K{sup +}-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

Hepatic vascular injury: Clinical profile, endovascular management and outcomes

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Bishav Mohan

2013-01-01

Conclusion: Prompt endovascular management is the modality of choice in comparison to NOM without AE in both pediatric and adult patients with hemodynamically compromised inaccessible intra hepatic vascular trauma.

Co-ultramicronized palmitoylethanolamide/luteolin promotes neuronal regeneration after spinal cord injury

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Rosalia eCrupi

2016-03-01

Full Text Available Spinal cord injury (SCI stimulates activation of astrocytes and infiltration of immune cells at the lesion site; however, the mechanism that promotes the birth of new neurons is still under debate. Neuronal regeneration is restricted after spinal cord injury, but can be stimulated by experimental intervention. Previously we demonstrated that treatment co-ultramicronized palmitoylethanolamide and luteolin, namely co-ultraPEALut, reduced inflammation. The present study was designed to explore the neuroregenerative properties of co-ultra PEALut in an estabished murine model of SCI. A vascular clip was applied to the spinal cord dura at T5 to T8 to provoke injury. Mice were treated with co-ultraPEALut (1 mg/kg, intraperitoneally daily for 72 h after SCI. Co-ultraPEALut increased the numbers of both bromodeoxyuridine-positive nuclei and doublecortin-immunoreactive cells in the spinal cord of injured mice. To correlate neuronal development with synaptic plasticity a Golgi method was employed to analyze dendritic spine density. Co-ultraPEALut administration stimulated expression of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, nerve growth factor and neurotrophin-3. These findings show a prominent effect of co-ultraPEALut administration in the management of survival and differentiation of new neurons and spine maturation, and may represent a therapeutic treatment for spinal cord and other traumatic diseases.

The hepatic stellate cell in sight : targeting antiproliferative drugs to the fibrotic liver

NARCIS (Netherlands)

Greupink, Albert Hendrikus

2006-01-01

Liver fibrosis is characterized by the accumulation of excessive amounts of scar tissue in response to chronic liver injury. Important causes of chronic liver injury are viral hepatitis, metabolic disorders such as Wilson’s disease, autoimmune diseases and chronic exposure to certain chemicals,

Injury due to thorotrast

International Nuclear Information System (INIS)

Mori, Takesaburo

1976-01-01

A synthetic study was performed on some of those to whom Thorotrast had been injected, in Japan. In the epidemiological study of 147 war woundeds to whom Thorotrast had been injected, it was noted that the Thorotrast injection increased the mortality rate and the incidences of malignant hepatic tumor, liver cirrhosis, and hematological diseases. Clinical study of 44 of them showed that the Thorotrast injection resulted in liver and hematopoietic hypofunctions. Analysis of the dissection of the injected area in 118 cases showed malignant hepatic tumor in 63.5%, liver cirrhosis in 14.4% and hematological diseases in 10.2%. The total of the three types of disease was 88.1%. Histological classification showed that of the malignant hepatic tumors due to Thorotrast, hepatobiliary cancer and hemangioendothelioma of the liver were frequent. By the comparison of the absorbed dose in the liver of the malignant hepatic tumors due to Thorotrast with that of the cancers developed in animal experiments, it was noted that the carcinogenic dose was a mean of 2,000 - 3,000 rad by accumulated dose. It was elucidated that carcinogenesis and fibrination were primary in injury due to Thorotrast, i.e., late injury due to Thorotrast, and that the increase in the accumulated dose in rogans and the increase of the local dose due to the gigantic growth of Thorotrast granules in organs greatly influenced carninogenesis and fibrination. (Chiba, N.)

Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver.

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Osman, Rashid H; Liu, Long; Xia, Lili; Zhao, Xing; Wang, Qianqian; Sun, Xiaoxian; Zhang, Yihui; Yang, Biao; Zheng, Yun; Gong, Daoqing; Geng, Tuoyu

2016-07-01

Global prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes a threat to human health. Goose is a unique model of NAFLD for discovering therapeutic targets as its liver can develop severe steatosis without overt injury. Fatty acid desaturase (Fads) is a potential therapeutic target as Fads expression and mutations are associated with liver fat. Here, we hypothesized that Fads was promoted to provide a protection for goose fatty liver. To test this, goose Fads1 and Fads2 were sequenced. Fads1/2/6 expression was determined in goose liver and primary hepatocytes by quantitative PCR. Liver fatty acid composition was also analyzed by gas chromatography. Data indicated that hepatic Fads1/2/6 expression was gradually increased with the time of overfeeding. In contrast, trans-C18:1n9 fatty acid (Fads inhibitor) was reduced. However, enhanced Fads capacity for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis was not sufficient to compensate for the depleted LC-PUFAs in goose fatty liver. Moreover, cell studies showed that Fads1/2/6 expression was regulated by fatty liver-associated factors. Together, these findings suggest Fads1/2 as protective components are promoted to meet instant need for LC-PUFAs in goose fatty liver, and we propose this is required for severe hepatic steatosis without liver injury.

Post-injury stretch promotes recovery in a rat model of muscle damage induced by lengthening contractions.

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Mori, Tomohiro; Agata, Nobuhide; Itoh, Yuta; Inoue-Miyazu, Masumi; Mizumura, Kazue; Sokabe, Masahiro; Taguchi, Toru; Kawakami, Keisuke

2017-06-30

We investigated the cellular mechanisms and therapeutic effect of post-injury stretch on the recovery process from muscle injury induced by lengthening contractions (LC). One day after LC, a single 15-min bout of muscle stretch was applied at an intensity of 3 mNm. The maximal isometric torque was measured before and at 2-21 days after LC. The myofiber size was analyzed at 21 days after LC. Developmental myosin heavy chain-immunoreactive (dMHC-ir) cells, a marker of regenerating myofibers, were observed in the early recovery stage (2-5 days after LC). We observed that LC-induced injury markedly decreased isometric torque and myofiber size, which recovered faster in rats that underwent stretch than in rats that did not. Regenerating myofiber with dMHC-ir cells was observed earlier in rats that underwent stretch. These results indicate that post-injury stretch may facilitate the regeneration and early formation of new myofibers, thereby promoting structural and functional recovery from LC-induced muscle injury.

Hepatic Shock Differential Diagnosis and Risk Factors: A Review Article.

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Soleimanpour, Hassan; Safari, Saeid; Rahmani, Farzad; Nejabatian, Arezu; Alavian, Seyed Moayed

2015-10-01

Liver as an important organ has a vital role in physiological processes in the body. Different causes can disrupt normal function of liver. Factors such as hypo-perfusion, hypoxemia, infections and some others can cause hepatic injury and hepatic shock. Published research resources from 2002 to May 2015 in some databases (PubMed, Scopus, Index Copernicus, DOAJ, EBSCO-CINAHL, Science direct, Cochrane library and Google scholar and Iranian search database like SID and Iranmedex) were investigated for the present study. Different causes can lead to hepatic shock. Most of these causes can be prevented by early resuscitation and treatment of underlying factors. Hepatic shock is detected in ill patients, especially those with hemodynamic disorders. It can be prevented by early treatment of underlying disease. There is no definite treatment for hepatic shock and should be managed conservatively. Hepatic shock in patients can increase the mortality rate.

[Study on the effect of promoting intelligence development and preventing hypoxia/reoxygenation injury of selenium-banqiao-Codonopsis pilosula-overground part in mice].

Science.gov (United States)

Xiao, Benjian; Chen, Guodong; Lan, Zongping

2005-08-01

To study on the effect of promoting intelligence development and preventing Hypoxia/Reoxygenation injury of Selenium-Banqiao-Codonopsis pilosula-overground part in mice. Promoting Intelligence Development experiment was induced by PIA; Hypoxia/reoxygenation ingury model was established to observe the activity of ROS, SOD, MOD and CAT in blood. Selenium-Banqiao-Codonopsis pilosula-overground part could enhance the learning and memory ability of old mice and obviously extend the swimming time of mice. It could also decrease the quality of ROS and MDA, increase the activity of SOD, but no significant effect on CAT. Selenium-Banqiao-Codonopsis pilosula-overground part has effect on promoting intelligence development and preventing hypoxia/reoxygenation injury.

Complications of high grade liver injuries: management and outcomewith focus on bile leaks

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Bala Miklosh

2012-03-01

Full Text Available Abstract Background Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to expect an increased risk of hepatic complications following trauma. The aim of the current study was to define hepatic related morbidity in patients sustaining high-grade hepatic injuries that could be safely managed non-operatively. Patients and methods This is a retrospective study of patients with liver injury admitted to Hadassah-Hebrew University Medical Centre over a 10-year period. Grade 3-5 injuries were considered to be high grade. Collected data included the number and types of liver-related complications. Interventions which were required for these complications in patients who survived longer than 24 hours were analysed. Results Of 398 patients with liver trauma, 64 (16% were found to have high-grade liver injuries. Mechanism of injury was blunt trauma in 43 cases, and penetrating in 21. Forty patients (62% required operative treatment. Among survivors 22 patients (47.8% developed liver-related complications which required additional interventional treatment. Bilomas and bile leaks were diagnosed in 16 cases post-injury. The diagnosis of bile leaks was suspected with abdominal CT scan, which revealed intraabdominal collections (n = 6, and ascites (n = 2. Three patients had continuous biliary leak from intraabdominal drains left after laparotomy. Nine patients required ERCP with biliary stent placement, and 2 required percutaneous transhepatic biliary drainage. ERCP failed in one case. Four angioembolizations (AE were performed in 3 patients for rebleeding. Surgical treatment was found to be associated with higher complication rate. AE at admission was associated with a significantly higher rate of biliary complications. There were 24 deaths (37%, the majority from uncontrolled haemorrhage (18 patients. There were only 2 hepatic-related mortalities due to liver failure

Complications of high grade liver injuries: management and outcomewith focus on bile leaks.

Science.gov (United States)

Bala, Miklosh; Gazalla, Samir Abu; Faroja, Mohammad; Bloom, Allan I; Zamir, Gideon; Rivkind, Avraham I; Almogy, Gidon

2012-03-23

Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to expect an increased risk of hepatic complications following trauma. The aim of the current study was to define hepatic related morbidity in patients sustaining high-grade hepatic injuries that could be safely managed non-operatively. This is a retrospective study of patients with liver injury admitted to Hadassah-Hebrew University Medical Centre over a 10-year period. Grade 3-5 injuries were considered to be high grade. Collected data included the number and types of liver-related complications. Interventions which were required for these complications in patients who survived longer than 24 hours were analysed. Of 398 patients with liver trauma, 64 (16%) were found to have high-grade liver injuries. Mechanism of injury was blunt trauma in 43 cases, and penetrating in 21. Forty patients (62%) required operative treatment. Among survivors 22 patients (47.8%) developed liver-related complications which required additional interventional treatment. Bilomas and bile leaks were diagnosed in 16 cases post-injury. The diagnosis of bile leaks was suspected with abdominal CT scan, which revealed intraabdominal collections (n = 6), and ascites (n = 2). Three patients had continuous biliary leak from intraabdominal drains left after laparotomy. Nine patients required ERCP with biliary stent placement, and 2 required percutaneous transhepatic biliary drainage. ERCP failed in one case. Four angioembolizations (AE) were performed in 3 patients for rebleeding. Surgical treatment was found to be associated with higher complication rate. AE at admission was associated with a significantly higher rate of biliary complications. There were 24 deaths (37%), the majority from uncontrolled haemorrhage (18 patients). There were only 2 hepatic-related mortalities due to liver failure. A high complication rate following high-grade liver injuries should

Working mechanisms of a behavioural intervention promoting physical activity in persons with subacute spinal cord injury

NARCIS (Netherlands)

Nooijen, Carla F. J.; Stam, Henk J.; Schoenmakers, Imte; Sluis, Tebbe; Post, Marcel; Twisk, Jos; van den Berg-Emons, Rita J. G.

OBJECTIVE: In order to unravel the working mechanisms that underlie the effectiveness of a behavioural intervention promoting physical activity in persons with subacute spinal cord injury, the aim of this study was to assess the mediating effects of physical and psychosocial factors on the

Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils.

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Park, S; Kang, S; Kim, D S; Shin, B K; Moon, N R; Daily, J W

2014-08-01

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.

Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury.

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Zareen, N; Shinozaki, M; Ryan, D; Alexander, H; Amer, A; Truong, D Q; Khadka, N; Sarkar, A; Naeem, S; Bikson, M; Martin, J H

2017-11-01

Cervical injuries are the most common form of SCI. In this study, we used a neuromodulatory approach to promote skilled movement recovery and repair of the corticospinal tract (CST) after a moderately severe C4 midline contusion in adult rats. We used bilateral epidural intermittent theta burst (iTBS) electrical stimulation of motor cortex to promote CST axonal sprouting and cathodal trans-spinal direct current stimulation (tsDCS) to enhance spinal cord activation to motor cortex stimulation after injury. We used Finite Element Method (FEM) modeling to direct tsDCS to the cervical enlargement. Combined iTBS-tsDCS was delivered for 30min daily for 10days. We compared the effect of stimulation on performance in the horizontal ladder and the Irvine Beattie and Bresnahan forepaw manipulation tasks and CST axonal sprouting in injury-only and injury+stimulation animals. The contusion eliminated the dorsal CST in all animals. tsDCS significantly enhanced motor cortex evoked responses after C4 injury. Using this combined spinal-M1 neuromodulatory approach, we found significant recovery of skilled locomotion and forepaw manipulation skills compared with injury-only controls. The spared CST axons caudal to the lesion in both animal groups derived mostly from lateral CST axons that populated the contralateral intermediate zone. Stimulation enhanced injury-dependent CST axonal outgrowth below and above the level of the injury. This dual neuromodulatory approach produced partial recovery of skilled motor behaviors that normally require integration of posture, upper limb sensory information, and intent for performance. We propose that the motor systems use these new CST projections to control movements better after injury. Copyright © 2017 Elsevier Inc. All rights reserved.

IL-23 Promotes Myocardial I/R Injury by Increasing the Inflammatory Responses and Oxidative Stress Reactions

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Xiaorong Hu

2016-05-01

Full Text Available Background/Aims: Inflammation and oxidative stress play an important role in myocardial ischemia and reperfusion (I/R injury. We hypothesized that IL-23, a pro-inflammatory cytokine, could promote myocardial I/R injury by increasing the inflammatory response and oxidative stress. Methods: Male Sprague-Dawley rats were randomly assigned into sham operated control (SO group, ischemia and reperfusion (I/R group, (IL-23 + I/R group and (anti-IL-23 + I/R group. At 4 h after reperfusion, the serum concentration of lactate dehydrogenase (LDH, creatine kinase (CK and the tissue MDA concentration and SOD activity were measured. The infarcte size was measured by TTC staining. Apoptosis in heart sections were measured by TUNEL staining. The expression of HMGB1 and IL-17A were detected by Western Blotting and the expression of TNF-α and IL-6 were detected by Elisa. Results: After 4 h reperfusion, compared with the I/R group, IL-23 significantly increased the infarct size, the apoptosis of cardiomyocytes and the levels of LDH and CK (all P 0.05. All these effects were abolished by anti-IL-23 administration. Conclusion: The present study suggested that IL-23 may promote myocardial I/R injury by increasing the inflammatory responses and oxidative stress reaction.

First report of hepatic hematoma after presumed Bothrops envenomation

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Fernanda Cristina Cunha

2015-10-01

Full Text Available ABSTRACTIn Latin America, Bothrops envenomation is responsible for the majority of accidents caused by venomous snakes. Patients usually present local edema, bleeding and coagulopathy. Visceral hemorrhage is extremely rare and considered a challenge for diagnosis and management. We report the first case of hepatic hematoma owing to the bothropic envenomation in a 66-year-old man who was bitten in the left leg. He presented local edema, coagulopathy, and acute kidney injury. Radiological findings suggested hepatic hematoma, with a volume of almost 3 liters. The hepatic hematoma was gradually absorbed without the need for surgical intervention with complete resolution in 8 months.

Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89 and L. reuteri GMNL-263 ameliorate hepatic injuries in lupus-prone mice.

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Hsu, Tsai-Ching; Huang, Chih-Yang; Liu, Chung-Hsien; Hsu, Kuo-Ching; Chen, Yi-Hsing; Tzang, Bor-Show

2017-04-01

Probiotics are known to regulate host immunity by interacting with systemic and mucosal immune cells as well as intestinal epithelial cells. Supplementation with certain probiotics has been reported to be effective against various disorders, including immune-related diseases. However, little is known about the effectiveness of Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263) in the management of autoimmune diseases, especially systemic lupus erythematosus (SLE). NZB/W F1 mice, which are a lupus-prone animal model, were orally gavaged with GMNL-32, GMNL-89 or GMNL-263 to investigate the effects of these Lactobacillus strains on liver injuries in NZB/W F1 mice. The results thus obtained reveal that supplementary GMNL-32, GMNL-89 or GMNL-263 in NZB/W F1 mice ameliorates hepatic apoptosis and inflammatory indicators, such as matrix metalloproteinase-9 activity and C-reactive protein and inducible nitric oxide synthase expressions. In addition, supplementation with GMNL-32, GMNL-89 or GMNL-263 in NZB/W F1 mice reduced the expressions of hepatic IL-1β, IL-6 and TNF-α proteins by suppressing the mitogen-activated protein kinase and NF-κB signalling pathways. These findings, presented here for the first time, reveal that GMNL-32, GMNL-89 and GMNL-263 mitigate hepatic inflammation and apoptosis in lupus-prone mice and may support an alternative remedy for liver disorders in cases of SLE.

A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation

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Malte Bachmann

2018-02-01

Full Text Available Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP]-induced acute liver injury (ALI not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.

The Effect of Emodin-Assisted Early Enteral Nutrition on Severe Acute Pancreatitis and Secondary Hepatic Injury

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Gang Wang

2007-01-01

Full Text Available Severe acute pancreatitis (SAP characterized by atrocious progression and numerous complications often leads to a high mortality rate due to hypermetabolism, systemic inflammatory response syndrome (SIRS, and multiple organs dysfunction syndrome (MODS. Studies have revealed that both early enteral nutrition (EEN and emodin are potent agents in the management of SAP. However, whether the combined strategy is rational and more effective than either one alone remains unknown. In this regard, Wistar rats were treated with emodin-assisted EEN (EAEEN through enteral nutrient tubes after induction of SAP by retrograde infusion of 5.0% sodium taurocholate into the common pancreatic duct. Serum levels of amylase, tumor necrosis factor-alpha (TNF-α, angiotensin II (AngII, maleic dialdehyde (MDA, glutamic pyruvic transaminase (ALT, glutamic oxaloacetic transaminase (AST and C-reactive protein (CRP, intestinal secretory IgA (SIgA, pancreatic and hepatic myeloperoxidase (MPO activity as well as plasma levels of D-lactate and endotoxin were measured. In addition, pathologic alterations of pancreas and liver were observed microscopically. We found that EAEEN could significantly ameliorate these parameters and prevent pancreas and liver from serious damage. In conclusion, Our results indicated that EAEEN could exert beneficial effects on experimental SAP and obviously abate the severity of secondary hepatic injury. The combined strategy was safe and more effective than either one alone in the acute stage of SAP. This study also provided an experimental base for the clinical treatment of SAP patients with EAEEN.

[The catalase inhibitor aminotriazole alleviates acute alcoholic liver injury].

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Ai, Qing; Ge, Pu; Dai, Jie; Liang, Tian-Cai; Yang, Qing; Lin, Ling; Zhang, Li

2015-02-25

In this study, the effects of catalase (CAT) inhibitor aminotriazole (ATZ) on alcohol-induced acute liver injury were investigated to explore the potential roles of CAT in alcoholic liver injury. Acute liver injury was induced by intraperitoneal injection of alcohol in Sprague Dawley (SD) rats, and various doses of ATZ (100-400 mg/kg) or vehicle were administered intraperitoneally at 30 min before alcohol exposure. After 24 h of alcohol exposure, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in plasma were determined. The degree of hepatic histopathological abnormality was observed by HE staining. The activity of hepatic CAT, hydrogen peroxide (H₂O₂) level and malondialdehyde (MDA) content in liver tissue were measured by corresponding kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma were determined by ELISA method. The results showed that treatment with ATZ dose-dependently suppressed the elevation of ALT, AST and LDH levels induced by alcohol exposure, and that ATZ alleviated alcohol-induced histopathological alterations. Furthermore, ATZ inhibited the activity of CAT, reduced hepatic levels of H₂O₂and MDA in alcohol exposed rats. ATZ also decreased the levels of plasma TNF-α and IL-6 in rats with alcohol exposure. These results indicated that ATZ attenuated alcohol-induced acute liver injury in rats, suggesting that CAT might play important pathological roles in the pathogenesis of alcoholic liver injury.

Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training

Science.gov (United States)

Zou, Jun; Li, Zhili; Tian, Jijing; She, Ruiping; Wang, Desheng; Wang, Huijuan; Lv, Dongqiang; Chang, Lingling

2015-01-01

This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (ptraining slightly improved hepatic damage. PMID:26000905

Prevention of hepatitis B

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Marta Estera Kowalska

2017-07-01

Full Text Available Hepatitis B (Hepatitis B is a hepatitis B virus (HBV -based liver disease. This virus has an affinity for liver cells, it can cause both acute and chronic viral infections of varying severity. The consequences of chronic HBV infection can be cirrhosis and liver cancer. In Poland in 1989 a preventive program was implemented to reduce HBV infection. Universal vaccinations have been introduced to reduce the prevalence of Type B hepatitis B from 40.3 / 100,000 in 1989 to 7/100 in 2000. In the last 20 years in Poland there has been huge progress in the prevention and suppression of HBV infections. Decrease in the incidence of hepatitis B is mainly the result of the introduction of compulsory vaccination and improving hygiene procedures and improve sanitation aimed at aborting the pathways of the virus. However, still a large part of society is not immune on HBV infection acting potential group of the risk of infection. In addition, in the era of a growing group of followers. movements of the anti vaccine it is necessary to continue to promote knowledge of HBV and the efficacy and safety of vaccination.

Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline.

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McMillin, Matthew; Frampton, Gabriel; Thompson, Michelle; Galindo, Cheryl; Standeford, Holly; Whittington, Eric; Alpini, Gianfranco; DeMorrow, Sharon

2014-07-10

Acute liver failure leads to systemic complications with one of the most dangerous being a decline in neurological function, termed hepatic encephalopathy. Neurological dysfunction is exacerbated by an increase of toxic metabolites in the brain that lead to neuroinflammation. Following various liver diseases, hepatic and circulating chemokines, such as chemokine ligand 2 (CCL2), are elevated, though their effects on the brain following acute liver injury and subsequent hepatic encephalopathy are unknown. CCL2 is known to activate microglia in other neuropathies, leading to a proinflammatory response. However, the effects of CCL2 on microglia activation and the pathogenesis of hepatic encephalopathy following acute liver injury remain to be determined. Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) in the presence or absence of INCB 3284 dimesylate (INCB), a chemokine receptor 2 inhibitor, or C 021 dihydrochloride (C021), a chemokine receptor 4 inhibitor. Mice were monitored for neurological decline and time to coma (loss of all reflexes) was recorded. Tissue was collected at coma and used for real-time PCR, immunoblots, ELISA, or immunostaining analyses to assess the activation of microglia and consequences on pro-inflammatory cytokine expression. Following AOM administration, microglia activation was significantly increased in AOM-treated mice compared to controls. Concentrations of CCL2 in the liver, serum, and cortex were significantly elevated in AOM-treated mice compared to controls. Systemic administration of INCB or C021 reduced liver damage as assessed by serum liver enzyme biochemistry. Administration of INCB or C021 significantly improved the neurological outcomes of AOM-treated mice, reduced microglia activation, reduced phosphorylation of ERK1/2, and alleviated AOM-induced cytokine upregulation. These findings suggest that CCL2 is elevated systemically following acute liver injury and that CCL2 is involved in both the

Preventive effects of indole-3-carbinol against alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms: Role of gut-liver-adipose tissue axis.

Science.gov (United States)

Choi, Youngshim; Abdelmegeed, Mohamed A; Song, Byoung-Joon

2018-05-01

Indole-3-carbinol (I3C), found in Brassica family vegetables, exhibits antioxidant, anti-inflammatory, and anti-cancerous properties. Here, we aimed to evaluate the preventive effects of I3C against ethanol (EtOH)-induced liver injury and study the protective mechanism(s) by using the well-established chronic-plus-binge alcohol exposure model. The preventive effects of I3C were evaluated by conducting various histological, biochemical, and real-time PCR analyses in mouse liver, adipose tissue, and colon, since functional alterations of adipose tissue and intestine can also participate in promoting EtOH-induced liver damage. Daily treatment with I3C alleviated EtOH-induced liver injury and hepatocyte apoptosis, but not steatosis, by attenuating elevated oxidative stress, as evidenced by the decreased levels of hepatic lipid peroxidation, hydrogen peroxide, CYP2E1, NADPH-oxidase, and protein acetylation with maintenance of mitochondrial complex I, II, and III protein levels and activities. I3C also restored the hepatic antioxidant capacity by preventing EtOH-induced suppression of glutathione contents and mitochondrial aldehyde dehydrogenase-2 activity. I3C preventive effects were also achieved by attenuating the increased levels of hepatic proinflammatory cytokines, including IL1β, and neutrophil infiltration. I3C also attenuated EtOH-induced gut leakiness with decreased serum endotoxin levels through preventing EtOH-induced oxidative stress, apoptosis of enterocytes, and alteration of tight junction protein claudin-1. Furthermore, I3C alleviated adipose tissue inflammation and decreased free fatty acid release. Collectively, I3C prevented EtOH-induced liver injury via attenuating the damaging effect of ethanol on the gut-liver-adipose tissue axis. Therefore, I3C may also have a high potential for translational research in treating or preventing other types of hepatic injury associated with oxidative stress and inflammation. Copyright © 2017 Elsevier Inc. All

Recent advances in hepatic encephalopathy [version 1; referees: 4 approved

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Victoria Liere

2017-09-01

Full Text Available Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy. A literature search using the PubMed database was conducted in May 2017 using “hepatic encephalopathy” as a keyword, and selected manuscripts were limited to those research articles published since May 2014. While the authors acknowledge that many significant advances have been made in the understanding of hepatic encephalopathy prior to May 2014, we have limited the scope of this review to the previous three years only.

Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

DEFF Research Database (Denmark)

Schmidt, Lars E; Dalhoff, Kim

2005-01-01

An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...

Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis.

Science.gov (United States)

Kim, KyeongJin; Ryu, Dongryeol; Dongiovanni, Paola; Ozcan, Lale; Nayak, Shruti; Ueberheide, Beatrix; Valenti, Luca; Auwerx, Johan; Pajvani, Utpal B

2017-12-01

and in liver biopsies patients with NAFLD, compared with liver tissues from healthy control mice or patients without steatosis. Knockdown of KCTD17 with small hairpin RNA in primary hepatocytes increased PHLPP2 protein but not Phlpp2 mRNA, indicating that KCTD17 mediates PHLPP2 degradation. KCTD17 knockdown in obese mice prevented PHLPP2 degradation and decreased expression of lipogenic genes. In mouse models of obesity, we found that PHLPP2 degradation induced lipogenesis without affecting gluconeogenesis. KCTD17, which is up-regulated in liver tissues of obese mice and patients with NAFLD, binds to phosphorylated PHLPP2 to target it for ubiquitin-mediated degradation; this increases expression of genes that regulate lipogenesis to promote hepatic steatosis. Inhibitors of this pathway might be developed for treatment of patients with NAFLD. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Faktor Risiko Hepatitis B Pada Tenaga Kesehatan Kota Pekanbaru

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Rina Amtarina

2014-10-01

Full Text Available Hepatitis B is still the one of serious public health problem in the world including Indonesia. Transmission of hepatitis B virus (HBV is strongly associated with use of contaminated blood products. For many people infected with HBV, risk factors of transmission are unknown. We examined risk factors for acquiring HBV in health care worker. This research was done by retrospective to blood participants who tested positive for HBs antibody or HBs antigen, using a questionnaire.participants divided into 2 groups. Had/having exposed to VHB with ati-HBs Positive HBsag negative or HBsag positive, anti-HBs negative and never had exposed to VHB with HBsag and anti-HBs negative. Positive anti- HBs were identified in 32 (29.1% of 110 participants. Positive HBs antigen anti-HBs negative was identified in 1 (0.9% of 110 participants. In questionnaire analysis, significant risk factors for HBV infection among HBs antibody - positive participants were tooth extraction in 29 (90.6%, and needle stick injuries in 18 (56.2% of 32 participants. Only 3 (9.3% of 32 participants with HBs antibody - positive had history of post infected HBV for several years ago. In 1 participant with HBs antigen - positive, significant risk factors were needle stick injuries, acupuncture, tooth extraction, and contact infected person. The most significant risk factors for transmission of hepatitis B in health care worker in Pekanbaru city are tooth extraction and needle stick injuries.

Hepatic hydrothorax after blunt chest trauma

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Shang-Chiung Wang

2012-08-01

Full Text Available We report a successful treatment result in a rare case of hepatitis C virus-related cirrhosis, who had sustained hydrothorax after blunt thoracoabdominal trauma. This was a female patient with liver cirrhosis, Child–Turcotte–Pugh class A, without ascites before injury. She sustained blunt thoracoabdominal trauma with a left clavicle fracture dislocation and right rib fractures. There was no hemopneumothorax at initial presentation. However, dyspnea and right pleural effusion developed gradually. We inserted a chest tube to relieve the patient's symptoms, and the daily drainage amount remained consistent. Hepatic hydrothorax was confirmed by the intraperitoneal injection of radioisotope 99mTc-sulfur colloid that demonstrated one-way transdiaphragmatic flow of fluid from the peritoneal cavity to pleural cavities. Finally, the hydrothorax was treated successfully by minocycline-induced pleural symphysis. To the best of our knowledge, this is the first case of hepatic hydrothorax developed after thoracoabdominal trauma.

Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats

International Nuclear Information System (INIS)

Rodrigues, L.P.; Iglesias, D.; Nicola, F.C.; Steffens, D.; Valentim, L.; Witczak, A.; Zanatta, G.; Achaval, M.; Pranke, P.; Netto, C.A.

2011-01-01

Cell transplantation is a promising experimental treatment for spinal cord injury. The aim of the present study was to evaluate the efficacy of mononuclear cells from human umbilical cord blood in promoting functional recovery when transplanted after a contusion spinal cord injury. Female Wistar rats (12 weeks old) were submitted to spinal injury with a MASCIS impactor and divided into 4 groups: control, surgical control, spinal cord injury, and one cell-treated lesion group. Mononuclear cells from umbilical cord blood of human male neonates were transplanted in two experiments: a) 1 h after surgery, into the injury site at a concentration of 5 x 10 6 cells diluted in 10 µL 0.9% NaCl (N = 8-10 per group); b) into the cisterna magna, 9 days after lesion at a concentration of 5 x 10 6 cells diluted in 150 µL 0.9% NaCl (N = 12-14 per group). The transplanted animals were immunosuppressed with cyclosporin-A (10 mg/kg per day). The BBB scale was used to evaluate motor behavior and the injury site was analyzed with immunofluorescent markers to label human transplanted cells, oligodendrocytes, neurons, and astrocytes. Spinal cord injury rats had 25% loss of cord tissue and cell treatment did not affect lesion extension. Transplanted cells survived in the injured area for 6 weeks after the procedure and both transplanted groups showed better motor recovery than the untreated ones (P < 0.05). The transplantation of mononuclear cells from human umbilical cord blood promoted functional recovery with no evidence of cell differentiation

Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats

Energy Technology Data Exchange (ETDEWEB)

Rodrigues, L.P. [Programa de Pós-Graduação em Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Iglesias, D. [Laboratório de Hematologia e Células-Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Nicola, F.C. [Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Steffens, D. [Laboratório de Hematologia e Células-Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Valentim, L.; Witczak, A.; Zanatta, G. [Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Achaval, M. [Departamento de Ciências Morfológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Pranke, P. [Laboratório de Hematologia e Células-Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Netto, C.A. [Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)

2011-12-23

Cell transplantation is a promising experimental treatment for spinal cord injury. The aim of the present study was to evaluate the efficacy of mononuclear cells from human umbilical cord blood in promoting functional recovery when transplanted after a contusion spinal cord injury. Female Wistar rats (12 weeks old) were submitted to spinal injury with a MASCIS impactor and divided into 4 groups: control, surgical control, spinal cord injury, and one cell-treated lesion group. Mononuclear cells from umbilical cord blood of human male neonates were transplanted in two experiments: a) 1 h after surgery, into the injury site at a concentration of 5 x 10{sup 6} cells diluted in 10 µL 0.9% NaCl (N = 8-10 per group); b) into the cisterna magna, 9 days after lesion at a concentration of 5 x 10{sup 6} cells diluted in 150 µL 0.9% NaCl (N = 12-14 per group). The transplanted animals were immunosuppressed with cyclosporin-A (10 mg/kg per day). The BBB scale was used to evaluate motor behavior and the injury site was analyzed with immunofluorescent markers to label human transplanted cells, oligodendrocytes, neurons, and astrocytes. Spinal cord injury rats had 25% loss of cord tissue and cell treatment did not affect lesion extension. Transplanted cells survived in the injured area for 6 weeks after the procedure and both transplanted groups showed better motor recovery than the untreated ones (P < 0.05). The transplantation of mononuclear cells from human umbilical cord blood promoted functional recovery with no evidence of cell differentiation.

Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

Science.gov (United States)

Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

2016-08-01

Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

Hepatic lesions that mimic metastasis on radiological imaging during chemotherapy for gastrointestinal malignancy: Recent updates

Energy Technology Data Exchange (ETDEWEB)

You, Sung Hye; Park, Beom Jin; Kim, Yeul Hong [Anam Hospital, Korea University College of Medicine, Seoul (Korea, Republic of)

2017-06-15

During chemotherapy in patients with gastrointestinal malignancy, the hepatic lesions may occur as chemotherapy-induced lesions or tumor-associated lesions, with exceptions for infectious conditions and other incidentalomas. Focal hepatic lesions arising from chemotherapy-induced hepatopathies (such as chemotherapy-induced sinusoidal injury and steatosis) and tumor-associated eosinophilic abscess should be considered a mimicker of metastasis in patients with gastrointestinal malignancy. Accumulating evidence suggests that chemotherapy for gastrointestinal malignancy in the liver has roles in both the therapeutic effects for hepatic metastasis and injury to the non-tumor bearing hepatic parenchyma. In this article, we reviewed the updated concept of chemotherapy-induced hepatopathies and tumor-associated eosinophilic abscess in the liver, focusing on the pathological and radiological findings. Awareness of the causative chemo-agent, pathophysiology, and characteristic imaging findings of these mimickers is critical for accurate diagnosis and avoidance of unnecessary exposure of the patient to invasive tissue-based diagnosis and operation.

Hiv, hepatitis b and hepatitis c in garbage scavengers of karachi

International Nuclear Information System (INIS)

Rauf, M.U.; Saleem, M.D.; Anwar, M.O.; Ahmed, G.; Memon, M.A.

2013-01-01

Objectives: To determine the seroprevalence of human immunodeficiency virus, hepatitis B and C, and to study the associated risk factors in garbage scavengers of Karachi. Methods: The cross-sectional study was performed in a colony inhabited by low socioeconomic garbage-collecting people. Data was collected from April to December 2011. After informed consent and pre-test counselling, a set of questions were asked from a questionnaire, and 5cc of blood was drawn for pathological testing. SPSS 18 was used for statistical analysis. Results: A total of 141 males agreed to participate in the study with a mean age of 21.33+-9.28 years. Most of the respondents (n=67; 47.5%) were in the age group 11-20 years; 86 (61%) were single; 89 (63%) were illiterate and 127 (90%) had a monthly income less than Rs.10,000. Prevalence of hepatitis B was 18.8% (n=22), followed by 8.5% (n=10) and 0.85% (n=1) of hepatitis C and HIV respectively. Besides, 108 (77%) collected needles/syringes and 76 (54%) got pricked more than once. Only 23 (16%) wore gloves while collecting garbage. Overall, 79 (56%) had a history of sexual contact; 18 (23%) had three or more partners. Conclusion: The important factors contributing to the high prevalence of hepatitis B and C were needle prick injuries, bare-handed/bare-footed collection of garbage, poor vaccination status, improper garbage disposal system and the site of waste collection. (author)

Blunt hepatic trauma: comparison between surgical and nonoperative treatment.

Science.gov (United States)

Zago, Thiago Messias; Pereira, Bruno Monteiro; Calderan, Thiago Rodrigues Araujo; Hirano, Elcio Shiyoiti; Rizoli, Sandro; Fraga, Gustavo Pereira

2012-01-01

To examine the outcomes of blunt hepatic trauma, and compare surgical and non-surgical treatment in patients admitted with hemodynamic stability and with no obvious indications of laparotomy. This is a retrospective study of cases admitted to a university teaching hospital between the years 2000 and 2010. Patients undergoing surgical treatment were divided into two groups: (a) all patients undergoing surgical treatment, and (b) patients with obvious need for surgery. In this period, 120 patients were admitted with blunt hepatic trauma. Sixty five patients (54.1%) were treated non-operatively and fifty five patients were operated upon. Patients treated non-operatively had better physiologic conditions on admission, demonstrated less severe injuries (except the grade of hepatic injury), received less blood components and had lower morbidity and mortality than the patients operated upon. Patients who underwent non-operative treatment had a lower need for blood transfusion but higher rates of complications and mortality than the patients operated upon. Patients who were operated upon, with no obvious indications for surgery, had higher rates of complication and mortality than patients not operated upon. A non-operative approach resulted in lower complications, a lower need for blood transfusions and lower mortality.

Central effects of humanin on hepatic triglyceride secretion.

Science.gov (United States)

Gong, Zhenwei; Su, Kai; Cui, Lingguang; Tas, Emir; Zhang, Ting; Dong, H Henry; Yakar, Shoshana; Muzumdar, Radhika H

2015-08-01

Humanin (HN) is an endogenous mitochondria-associated peptide that has been shown to protect against various Alzheimer's disease-associated insults, myocardial ischemia-reperfusion injury, and reactive oxygen species-induced cell death. We have shown previously that HN improves whole body glucose homeostasis by improving insulin sensitivity and increasing glucose-stimulated insulin secretion (GSIS) from the β-cells. Here, we report that intraperitoneal treatment with one of HN analogs, HNG, decreases body weight gain, visceral fat, and hepatic triglyceride (TG) accumulation in high-fat diet-fed mice. The decrease in hepatic TG accumulation is due to increased activity of hepatic microsomal triglyceride transfer protein (MTTP) and increased hepatic TG secretion. Both intravenous (iv) and intracerebroventricular (icv) infusion of HNG acutely increase TG secretion from the liver. Vagotomy blocks the effect on both iv and icv HNG on TG secretion, suggesting that the effects of HNG on hepatic TG flux are centrally mediated. Our data suggest that HN is a new player in central regulation of peripheral lipid metabolism. Copyright © 2015 the American Physiological Society.

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

Science.gov (United States)

Guo, Liang; Chen, Zhimin; Xia, Houjun; Li, Siming; Zhang, Yanqiao; Kobberup, Sune; Zou, Weiping; Lin, Jiandie D.

2017-01-01

Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue–enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus–mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury. PMID:29106384

Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control.

Science.gov (United States)

Carmel, Jason B; Kimura, Hiroki; Martin, John H

2014-01-08

Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To test motor skill, rats were trained and tested to walk on a horizontal ladder with irregularly spaced rungs. Eight weeks after injury, produced by pyramidal tract transection, half of the rats received forelimb motor cortex stimulation of the intact hemisphere. Rats with injury and stimulation had significantly improved forelimb control compared with rats with injury alone and achieved a level of proficiency similar to uninjured rats. To test whether recovery of forelimb function was attributable to ipsilateral control, we selectively inactivated the stimulated motor cortex using the GABA agonist muscimol. The dose of muscimol we used produces strong contralateral but no ipsilateral impairments in naive rats. In rats with injury and stimulation, but not those with injury alone, inactivation caused worsening of forelimb function; the initial deficit was reinstated. These results demonstrate that electrical stimulation can promote recovery of motor function when applied late after injury and that motor control can be exerted from the ipsilateral motor cortex. These results suggest that the uninjured motor cortex could be targeted for brain stimulation in people with large unilateral CST lesions.

Opuntia ficus-indica seed attenuates hepatic steatosis and promotes M2 macrophage polarization in high-fat diet-fed mice.

Science.gov (United States)

Kang, Jung-Woo; Shin, Jun-Kyu; Koh, Eun-Ji; Ryu, Hyojeong; Kim, Hyoung Ja; Lee, Sun-Mee

2016-04-01

Opuntia ficus-indica (L.) is a popular edible plant that possesses considerable nutritional value and exhibits diverse biological actions including anti-inflammatory and antidiabetic activities. In this study, we hypothesized that DWJ504, an extract of O ficus-indica seed, would ameliorate hepatic steatosis and inflammation by regulating hepatic de novo lipogenesis and macrophage polarization against experimental nonalcoholic steatohepatitis. Mice were fed a normal diet or a high-fat diet (HFD) for 10 weeks. DWJ504 (250, 500, and 1000 mg/kg) or vehicle (0.5% carboxymethyl cellulose) were orally administered for the last 4 weeks of the 10-week HFD feeding period. DWJ504 treatment remarkably attenuated HFD-induced increases in hepatic lipid content and hepatocellular damage. DWJ504 attenuated increases in sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein expression and a decrease in carnitine palmitoyltransferase 1A. Although DWJ504 augmented peroxisome proliferator-activated receptor α protein expression, it attenuated peroxisome proliferator-activated receptor γ expression. Moreover, DWJ504 promoted hepatic M2 macrophage polarization as indicated by attenuation of the M1 marker genes and enhancement of M2 marker genes. Finally, DWJ504 attenuated expression of toll-like receptor 4, nuclear factor κB, tumor necrosis factor α, interleukin 6, TIR-domain-containing adapter-inducing interferon β, and interferon β levels. Our results demonstrate that DWJ504 prevented intrahepatic lipid accumulation, induced M2 macrophage polarization, and suppressed the toll-like receptor 4-mediated inflammatory signaling pathway. Thus, DWJ504 has therapeutic potential in the prevention of nonalcoholic fatty liver disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Nonoperative management for patients with grade IV blunt hepatic trauma

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Zago Thiago

2012-08-01

Full Text Available Abstract Introduction The treatment of complex liver injuries remains a challenge. Nonoperative treatment for such injuries is increasingly being adopted as the initial management strategy. We reviewed our experience, at a University teaching hospital, in the nonoperative management of grade IV liver injuries with the intent to evaluate failure rates; need for angioembolization and blood transfusions; and in-hospital mortality and complications. Methods This is a retrospective analysis conducted at a single large trauma centre in Brazil. All consecutive, hemodynamically stable, blunt trauma patients with grade IV hepatic injury, between 1996 and 2011, were analyzed. Demographics and baseline characteristics were recorded. Failure of nonoperative management was defined by the need for surgical intervention. Need for angioembolization and transfusions, in-hospital death, and complications were also assessed Results Eighteen patients with grade IV hepatic injury treated nonoperatively during the study period were included. The nonoperative treatment failed in only one patient (5.5% who had refractory abdominal pain. However, no missed injuries and/or worsening of bleeding were observed during the operation. None of the patients died nor need angioembolization. No complications directly related to the liver were observed. Unrelated complications to the liver occurred in three patients (16.7%; one patient developed a tracheal stenosis (secondary to tracheal intubation; one had pleural effusion; and one developed an abscess in the pleural cavity. The hospital length of stay was on average 11.56 days. Conclusions In our experience, nonoperative management of grade IV liver injury for stable blunt trauma patients is associated with high success rates without significant complications.

Nonoperative management for patients with grade IV blunt hepatic trauma.

Science.gov (United States)

Zago, Thiago Messias; Tavares Pereira, Bruno Monteiro; Araujo Calderan, Thiago Rodrigues; Godinho, Mauricio; Nascimento, Bartolomeu; Fraga, Gustavo Pereira

2012-08-22

The treatment of complex liver injuries remains a challenge. Nonoperative treatment for such injuries is increasingly being adopted as the initial management strategy. We reviewed our experience, at a University teaching hospital, in the nonoperative management of grade IV liver injuries with the intent to evaluate failure rates; need for angioembolization and blood transfusions; and in-hospital mortality and complications. This is a retrospective analysis conducted at a single large trauma centre in Brazil. All consecutive, hemodynamically stable, blunt trauma patients with grade IV hepatic injury, between 1996 and 2011, were analyzed. Demographics and baseline characteristics were recorded. Failure of nonoperative management was defined by the need for surgical intervention. Need for angioembolization and transfusions, in-hospital death, and complications were also assessed Eighteen patients with grade IV hepatic injury treated nonoperatively during the study period were included. The nonoperative treatment failed in only one patient (5.5%) who had refractory abdominal pain. However, no missed injuries and/or worsening of bleeding were observed during the operation. None of the patients died nor need angioembolization. No complications directly related to the liver were observed. Unrelated complications to the liver occurred in three patients (16.7%); one patient developed a tracheal stenosis (secondary to tracheal intubation); one had pleural effusion; and one developed an abscess in the pleural cavity. The hospital length of stay was on average 11.56 days. In our experience, nonoperative management of grade IV liver injury for stable blunt trauma patients is associated with high success rates without significant complications.

Intraspinal Delivery of Polyethylene Glycol-coated Gold Nanoparticles Promotes Functional Recovery After Spinal Cord Injury.

Science.gov (United States)

Papastefanaki, Florentia; Jakovcevski, Igor; Poulia, Nafsika; Djogo, Nevena; Schulz, Florian; Martinovic, Tamara; Ciric, Darko; Loers, Gabrielle; Vossmeyer, Tobias; Weller, Horst; Schachner, Melitta; Matsas, Rebecca

2015-06-01

Failure of the mammalian central nervous system (CNS) to regenerate effectively after injury leads to mostly irreversible functional impairment. Gold nanoparticles (AuNPs) are promising candidates for drug delivery in combination with tissue-compatible reagents, such as polyethylene glycol (PEG). PEG administration in CNS injury models has received interest for potential therapy, but toxicity and low bioavailability prevents clinical application. Here we show that intraspinal delivery of PEG-functionalized 40-nm-AuNPs at early stages after mouse spinal cord injury is beneficial for recovery. Positive outcome of hind limb motor function was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons. No adverse effects, such as body weight loss, ill health, or increased mortality were observed. We propose that PEG-AuNPs represent a favorable drug-delivery platform with therapeutic potential that could be further enhanced if PEG-AuNPs are used as carriers of regeneration-promoting molecules.

Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury

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Jian-long Wang

2015-01-01

Full Text Available Hydrogen can relieve tissue-damaging oxidative stress, inflammation and apoptosis. Injection of hydrogen-rich saline is an effective method for transporting molecular hydrogen. We hypothesized that hydrogen-rich saline would promote the repair of spinal cord injury induced by Allen′s method in rats. At 0.5, 1, 2, 4, 8, 12 and 24 hours after injury, then once daily for 2 weeks, 0.25 mL/kg hydrogen-rich saline was infused into the subarachnoid space through a catheter. Results at 24 hours, 48 hours, 1 week and 2 weeks after injury showed that hydrogen-rich saline markedly reduced cell death, inflammatory cell infiltration, serum malondialdehyde content, and caspase-3 immunoreactivity, elevated serum superoxide dismutase activity and calcitonin gene-related peptide immunoreactivity, and improved motor function in the hindlimb. The present study confirms that hydrogen-rich saline injected within 2 weeks of injury effectively contributes to the repair of spinal cord injury in the acute stage.

Ibuprofen administration attenuates serum TNF-α levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

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Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina; Berson, Alain; Letteron, Philippe; Larosche, Isabelle; Descatoire, Veronique; Feldmann, Gerard; Robin, Marie-Anne; Pessayre, Dominique

2008-01-01

Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-α (TNF-α), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 μg/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-α. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-α secretion) and infliximab (trapping TNF-α) likewise attenuated the Jo2-mediated increase in TNF-α, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-α secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-α secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice

Identification of Antiviral Agents Targeting Hepatitis B Virus Promoter from Extracts of Indonesian Marine Organisms by a Novel Cell-Based Screening Assay

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Atsuya Yamashita

2015-11-01

Full Text Available The current treatments of chronic hepatitis B (CHB face a limited choice of vaccine, antibody and antiviral agents. The development of additional antiviral agents is still needed for improvement of CHB therapy. In this study, we established a screening system in order to identify compounds inhibiting the core promoter activity of hepatitis B virus (HBV. We prepared 80 extracts of marine organisms from the coral reefs of Indonesia and screened them by using this system. Eventually, two extracts showed high inhibitory activity (>95% and low cytotoxicity (66% to 77%. Solvent fractionation, column chromatography and NMR analysis revealed that 3,5-dibromo-2-(2,4-dibromophenoxy-phenol (compound 1 and 3,4,5-tribromo-2-(2,4-dibromophenoxy-phenol (compound 2, which are classified as polybrominated diphenyl ethers (PBDEs, were identified as anti-HBV agents in the extracts. Compounds 1 and 2 inhibited HBV core promoter activity as well as HBV production from HepG2.2.15.7 cells in a dose-dependent manner. The EC50 values of compounds 1 and 2 were 0.23 and 0.80 µM, respectively, while selectivity indexes of compound 1 and 2 were 18.2 and 12.8, respectively. These results suggest that our cell-based HBV core promoter assay system is useful to determine anti-HBV compounds, and that two PBDE compounds are expected to be candidates of lead compounds for the development of anti-HBV drugs.

Identification of Antiviral Agents Targeting Hepatitis B Virus Promoter from Extracts of Indonesian Marine Organisms by a Novel Cell-Based Screening Assay

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Yamashita, Atsuya; Fujimoto, Yuusuke; Tamaki, Mayumi; Setiawan, Andi; Tanaka, Tomohisa; Okuyama-Dobashi, Kaori; Kasai, Hirotake; Watashi, Koichi; Wakita, Takaji; Toyama, Masaaki; Baba, Masanori; de Voogd, Nicole J.; Maekawa, Shinya; Enomoto, Nobuyuki; Tanaka, Junichi; Moriishi, Kohji

2015-01-01

The current treatments of chronic hepatitis B (CHB) face a limited choice of vaccine, antibody and antiviral agents. The development of additional antiviral agents is still needed for improvement of CHB therapy. In this study, we established a screening system in order to identify compounds inhibiting the core promoter activity of hepatitis B virus (HBV). We prepared 80 extracts of marine organisms from the coral reefs of Indonesia and screened them by using this system. Eventually, two extracts showed high inhibitory activity (>95%) and low cytotoxicity (66% to 77%). Solvent fractionation, column chromatography and NMR analysis revealed that 3,5-dibromo-2-(2,4-dibromophenoxy)-phenol (compound 1) and 3,4,5-tribromo-2-(2,4-dibromophenoxy)-phenol (compound 2), which are classified as polybrominated diphenyl ethers (PBDEs), were identified as anti-HBV agents in the extracts. Compounds 1 and 2 inhibited HBV core promoter activity as well as HBV production from HepG2.2.15.7 cells in a dose-dependent manner. The EC50 values of compounds 1 and 2 were 0.23 and 0.80 µM, respectively, while selectivity indexes of compound 1 and 2 were 18.2 and 12.8, respectively. These results suggest that our cell-based HBV core promoter assay system is useful to determine anti-HBV compounds, and that two PBDE compounds are expected to be candidates of lead compounds for the development of anti-HBV drugs. PMID:26561821

Right Hepatic Artery: A Cadaver Investigation and Its Clinical Significance

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Usha Dandekar

2015-01-01

Full Text Available The right hepatic artery is an end artery and contributes sole arterial supply to right lobe of the liver. Misinterpretation of normal anatomy and anatomical variations of the right hepatic artery contribute to the major intraoperative mishaps and complications in hepatobiliary surgery. The frequency of inadvertent or iatrogenic hepatobiliary vascular injury rises with the event of an aberrant anatomy. This descriptive study was carried out to document the normal anatomy and different variations of right hepatic artery to contribute to existing knowledge of right hepatic artery to improve surgical safety. This study conducted on 60 cadavers revealed aberrant replaced right hepatic artery in 18.3% and aberrant accessory right hepatic artery in 3.4%. Considering the course, the right hepatic artery ran outside Calot’s triangle in 5% of cases and caterpillar hump right hepatic artery was seen in 13.3% of cases. The right hepatic artery (normal and aberrant crossed anteriorly to the common hepatic duct in 8.3% and posteriorly to it in 71.6%. It has posterior relations with the common bile duct in 16.7% while in 3.4% it did not cross the common hepatic duct or common bile duct. The knowledge of such anomalies is important since their awareness will decrease morbidity and help to keep away from a number of surgical complications.

The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury.

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Joshi, Nikita; Kopec, Anna K; Towery, Keara; Williams, Kurt J; Luyendyk, James P

2014-06-01

Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant α-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1(-/-) mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats

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Bunaciu, Rodica Petruta; Tharappel, Job C.; Lehmler, Hans-Joachim; Kania-Korwel, Izabela; Robertson, Larry W.; Srinivasan, Cidambi; Spear, Brett T.; Glauert, Howard P.

2007-01-01

Polychlorinated biphenyls (PCBs) are ubiquitious lipophilic environmental pollutants. Some of the PCB congeners and mixtures of congeners have tumor promoting activity in rat liver. The mechanism of their activity is not fully understood and is likely to be multifactorial. The aim of this study was to investigate if the resident liver macrophages, Kupffer cells, are important in the promoting activity of PCBs. The hypothesis of this study was that the inhibition of Kupffer cell activity would inhibit hepatic tumor promotion by PCBs in rats. To test our hypothesis, we studied the effects of Kupffer cell inhibition by dietary glycine (an inhibitor of Kupffer cell secretory activity) in a rat two-stage hepatocarcinogenesis model using 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153, a non-dioxin-like PCB) or 3,3',4,4'-tetrachlorobiphenyl (PCB-77, a dioxin-like PCB) as promoters. Diethylnitrosamine (DEN, 150 mg/kg) was administered to female Sprague-Dawley rats, which were then placed on an unrefined diet containing 5% glycine (or casein as nitrogen control) starting two weeks after DEN administration. On the third day after starting the diets, rats received PCB-77 (300 μmol/kg), PCB-153 (300 μmol/kg), or corn oil by i.p. injection. The rats received a total of 4 PCB injections, administered every 14 days. The rats were euthanized on the 10th day after the last PCB injection, and the formation of altered hepatic foci expressing placental glutathione S-transferase (PGST) and the rate of DNA synthesis in these foci and in the normal liver tissue were determined. Glycine did not significantly affect foci number or volume. PCB-153 did not significantly increase the focal volume, but increased the number of foci per liver, but only in the rats not fed glycine; PCB-77 increased both the foci number and their volume in both glycine-fed and control rats. Glycine did not alter the PCB content of the liver, but did increase the activity of 7-benzyloxyresorufin O-dealkylase (BROD

Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools

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Ritchie, D.G.

1990-01-01

Cytokines, derived from a wide variety of cell types, are now believed to initiate many of the physiological responses accompanying the inflammatory phase that follows either Gram-negative septicemia or thermal injury. Because hypoglycemia (after endotoxic challenge) and hyperglycemia (after thermal injury) represent well-characterized responses to these injuries, we sought to determine whether hepatic glycogen metabolism could be altered by specific cytokines. Cultured adult rat hepatocytes were prelabeled with [ 14 C]glucose for 24 h, a procedure that resulted in the labeling of hepatic glycogen pools that subsequently could be depleted (with concomitant [ 14 C]glucose release) by either glucagon or norepinephrine. After the addition of a highly concentrated human monocyte-conditioned medium (MCM) or various cytokines to these prelabeled cells, [ 14 C]glucose release was stimulated by MCM and recombinant human interleukin 6 (IL-6) but was not stimulated by other cytokines tested. Furthermore, only antisera to IL-6 were capable of reducing the glucose-releasing factor activity found in MCM. These data therefore suggest a novel glucoregulatory role for IL-6

Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.

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Desirée L Salazar

2010-08-01

Full Text Available Traumatic spinal cord injury (SCI results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+ and CD24(-/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.

Hepatic iron overload is associated with hepatocyte apoptosis during Clonorchis sinensis infection.

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Han, Su; Tang, Qiaoran; Chen, Rui; Li, Yihong; Shu, Jing; Zhang, Xiaoli

2017-08-01

Hepatic iron overload has been implicated in many liver diseases; however, whether it is involved in clonorchiasis remains unknown. The purpose of this study is to investigate whether Clonorchis sinensis (C. sinensis) infection causes hepatic iron overload, analyze the relationship between the iron overload and associated cell apoptosis, so as to determine the role of excess iron plays in C. sinensis-induced liver injury. The Perls' Prussian staining and atomic absorption spectrometry methods were used to investigate the iron overload in hepatic sections of wistar rats and patients infected with C. sinensis. The hepatic apoptosis was detected by transferase uridyl nick end labeling (TUNEL) methods. Spearman analysis was used for determining the correlation of the histological hepatic iron index and the apoptotic index. Blue iron particles were deposited mainly in the hepatocytes, Kupffer cells and endothelial cells, around the liver portal and central vein area of both patients and rats. The total iron score was found to be higher in the infected groups than the respective control from 8 weeks. The hepatic iron concentration was also significantly higher in treatment groups than in control rats from 8 weeks. The hepatocyte apoptosis was found to be significantly higher in the portal area of the liver tissue and around the central vein. However, spearman's rank correlation coefficient revealed that there was a mildly negative correlation between the iron index and hepatocyte apoptosis. This present study confirmed that hepatic iron overload was found during C. sinensis infection. This suggests that iron overload may be associated with hepatocyte apoptosis and involved in liver injury during C. sinensis infection. Further studies are needed to investigate the molecular mechanism involved here.

Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats

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Jian Hao

2017-01-01

Full Text Available Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of NeuN-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14–56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1β, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.

Evaluation of potential changes in liver and lung tissue of rats in an ischemia-reperfusion injury model (modified pringle maneuver.

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Silvio Henrique Freitas

Full Text Available In surgical procedures involving the liver, such as transplantation, resection, and trauma, a temporary occlusion of hepatic vessels may be required. This study was designed to analyze the lesions promoted by ischemia and reperfusion injury of the hepatic pedicle, in the liver and lung, using histopathological and immunohistochemical techniques. In total, 39 Wistar rats were divided into four groups: control group (C n = 3 and ischemia groups subjected to 10, 20, and 30 minutes of hepatic pedicle clamping (I10, n = 12; I20, n = 12; I30, n = 12. Each ischemia group was subdivided into four subgroups of reperfusion (R15, n = 3; R30, n = 3; R60, n = 3; R120, n = 3, after 15, 30, 60, and 120 minutes of reperfusion, respectively. Significant differences were observed in the liver parenchyma (P 0.05. In the lung parenchyma, a significant difference was observed (P 0.05 at different times of ischemia and reperfusion. In the pulmonary parenchyma, the immunoreactivity was not specific, and was not quantified. This study demonstrated that the longer the duration of ischemia and reperfusion, the greater are the morphological lesions found in the hepatic and pulmonary parenchyma.

Energy metabolism during activity-promoting video games practice in subjects with spinal cord injury: evidences for health promotion.

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Gaffurini, P; Bissolotti, L; Calza, S; Calabretto, C; Orizio, C; Gobbo, M

2013-02-01

Activity promoting video game (APVG) practice significantly affects energy metabolism through energy expenditure (EE) increase and has been recently included in strategies for health promotion. It is not known if the APVG practice provides similar outcomes in subjects with spinal cord injury (SCI). Aim of the study was to evaluate cardio-pulmonary and metabolic adaptations during APVG practice and to find whether EE increase above resting condition could suggest the inclusion of this exercise in a more general strategy for health promotion and body weight control in subjects with SCI. Repeated measures study. Rehabilitation Institute. Ten male subjects with SCI (lesion levels from C7 to L1) age 26 to 55 years. We recorded pulmonary ventilation (VE), oxygen consumption (VO2) for EE esteem and heart rate (HR) at rest and while playing virtual bowling, tennis and boxing games using a portable metabolimeter equipped with ECG electrodes. The standard metabolic equivalent of task (METs) was calculated offline. The metabolic and functional parameters were referred to the 10th minute of each activity. Metabolic and functional parameters increased significantly from rest to bowling, tennis and boxing. METs exceeded in average 3 during boxing. One hour of APVG can increase daily EE by about 6% (bowling), 10% (tennis) and 15% (boxing). These considerable results suggest that physical exertion during APVG practice in subjects with SCI could contribute to health promotion as well as caloric balance control, especially when boxing is considered. This can be safely achieved at home with regular activity. These findings substantiate the potential for novel exercise modalities to counteract deconditioning due to inactivity in subjects with SCI by promoting physical activity through implementation of APVG exercise programs.

Curcumin accelerates the repair of sciatic nerve injury in rats through reducing Schwann cells apoptosis and promoting myelinization.

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Zhao, Zhiwei; Li, Xiaoling; Li, Qing

2017-08-01

Schwann cells (SCs) play an indispensable role in the repair and regeneration of injured peripheral nerve. Curcumin can reduce SCs apoptosis, and promote the regeneration and functional recovery of injured peripheral nerves. However, the corresponding mechanisms are not clear. The article was aimed to explore the effect and corresponding mechanisms of curcumin on the repair of sciatic nerve injury in rats. After surgery induced sciatic nerve injury, the model rats were divided into three groups and treated with curcumin, curcumin+PD98059 and curcumin+IGF-1 respectively for 4days. The phosphorylation of Erk1/2 and Akt, and the expression of LC3-II, Beclin 1 and p62 were measured using western blotting. After treatment for 60days, myelination of the injured sciatic nerve was evaluated by MBP immunohistochemical staining and the expression of PMP22, Fibrin and S100 were determined using qRT-PCR and western blotting. In vitro, RSC96 cells were starved for 12h to induce autophagy, and received DMSO, curcumin, PD98059+curcumin, IGF-1+curcumin and BFA1 respectively. The phosphorylation of Erk1/2、Akt and the expression of LC3-II, Beclin 1, p62, PMP22, Fibrin and S100 were measured using western blotting, and the cell apoptosis was detected by flow cytometry. Curcumin could promote injury-induced cell autophagy, remyelination and axon regeneration in sciatic nerve of rats. In vitro, curcumin could accelerate cell autophagy through regulating autophagy related Erk1/2 and Akt pathway, prevent cell apoptosis and promote expression of PMP22 and S100, and reduced deposition of Fibrin in cultured RSC96 SCs. Curcumin could accelerate injured sciatic nerve repair in rats through reducing SCs apoptosis and promoting myelinization. Copyright © 2017. Published by Elsevier Masson SAS.

Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana.

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Osakunor, Derick Nii Mensah; Obirikorang, Christian; Fianu, Vincent; Asare, Isaac; Dakorah, Mavis

2015-01-01

Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients. A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher's, Chi-square, unpaired t-test and Pearson's correlation in analysis, using GraphPad Prism and SPSS. A P value 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p enzymes for both groups was small. Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients.

Methylprednisolone promotes recovery of neurological function after spinal cord injury: association with Wnt/β-catenin signaling pathway activation

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Lu, Gong-biao; Niu, Fu-wen; Zhang, Ying-chun; Du, Lin; Liang, Zhi-yuan; Gao, Yuan; Yan, Ting-zhen; Nie, Zhi-kui; Gao, Kai

2016-01-01

Some studies have indicated that the Wnt/β-catenin signaling pathway is activated following spinal cord injury, and expression levels of specific proteins, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β, are significantly altered. We hypothesized that methylprednisolone treatment contributes to functional recovery after spinal cord injury by inhibiting apoptosis and activating the Wnt/β-catenin signaling pathway. In the current study, 30 mg/kg methylprednisolone was injected into rats with spinal cord injury immediately post-injury and at 1 and 2 days post-injury. Basso, Beattie, and Bresnahan scores showed that methylprednisolone treatment significantly promoted locomotor functional recovery between 2 and 6 weeks post-injury. The number of surviving motor neurons increased, whereas the lesion size significantly decreased following methylprednisolone treatment at 7 days post-injury. Additionally, caspase-3, caspase-9, and Bax protein expression levels and the number of apoptotic cells were reduced at 3 and 7 days post-injury, while Bcl-2 levels at 7 days post-injury were higher in methylprednisolone-treated rats compared with saline-treated rats. At 3 and 7 days post-injury, methylprednisolone up-regulated expression and activation of the Wnt/β-catenin signaling pathway, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β phosphorylation. These results indicate that methylprednisolone-induced neuroprotection may correlate with activation of the Wnt/β-catenin signaling pathway. PMID:28123427

Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors.

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Alessandrino, F; Tirumani, S H; Krajewski, K M; Shinagare, A B; Jagannathan, J P; Ramaiya, N H; Di Salvo, D N

2017-07-01

The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Blunt abdominal trauma in adults: role of CT in the diagnosis and management of visceral injuries. Part 1. Liver and spleen

International Nuclear Information System (INIS)

Becker, C.D.; Terrier, F.; Mentha, G.

1998-01-01

Computed tomography is now widely used in the initial diagnostic workup of adult trauma victims with suspected intra-abdominal injuries. We review the role of CT in the detection and management of blunt visceral injuries in two parts. In the first part we discuss general aspects of performing CT in the setting of abdominal trauma and the diagnostic findings of intra-abdominal hemorrhage and blunt hepatic and splenic injuries. Hepatic and splenic injuries can be detected by means of CT with a high accuracy. The vast majority of hepatic injuries can be successfully managed conservatively, even when CT demonstrates parenchymal damage of more than three segments and major hemoperitoneum. Delayed complications, e. g., formation of biloma or a false aneurysm, can be readily detected on repeat CT studies, although they are quite uncommon. The outcome of conservative treatment of splenic injuries remains unpredictable because delayed splenic rupture may occur even when initial CT shows only minor parenchymal lesions and little or no intraperitoneal hemorrhage. (orig.)

Diphenhydramine as a Cause of Drug-Induced Liver Injury

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Yunseok Namn

2017-01-01

Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling.

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Yin, Huquan; Liang, Xiaomei; Jogasuria, Alvin; Davidson, Nicholas O; You, Min

2015-05-01

Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol-induced liver inflammation process is unknown. Here, we examined the role of miR-217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217-mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-κB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Hepatic trauma: CT findings and considerations based on our experience in emergency diagnostic imaging

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Romano, Luigia; Giovine, Sabrina; Guidi, Guido; Tortora, Giovanni; Cinque, Teresa; Romano, Stefania

2004-01-01

Abdominal blunt trauma represents the main cause of death in people of age less than 40 years; the liver injury occurs frequently, with an incidence varying from 3 to 10%. Isolated hepatic lesions are rare and in 77-90% of cases, lesions of other organs and viscera are involved. Right hepatic lobe is a frequent site of injury, because it is the more voluminous portion of liver parenchyma; posterior superior hepatic segments are proximal to fixed anatomical structures such as ribs and spine that may have an important role in determining of the lesion. The coronal ligaments' insertion in this parenchymal region augments the effect of acceleration-deceleration mechanism. Associated lesions usually are homolateral costal fractures, laceration or contusion of the inferior right pulmonary lobe, haemothorax, pneumothorax, renal and/or adrenal lesions. Traumatic lesions of left hepatic lobe are rare and usually associated with direct impact on the superior abdomen, such as in car-crash when the wheel causes a compressive effect on thorax and abdomen. Associated lesions to left hepatic lobe injuries correlated to this mechanism are: sternal fractures, pancreatic, myocardial, gastrointestinal tract injuries. Lesions of the caudal lobe are extremely rare, usually not isolated and noted with other large parenchymal lesions. The Institution of Specialized Trauma Centers and the technical progress in imaging methodology developed in the last years a great reduction of mortality. New diagnostic methodologies allow a reduction of negatives laparotomies and allow the possibility of conservative treatment of numerous traumatic lesions; however, therapy depends from imaging findings and clinical conditions of the patient. Computed tomography (CT) certainly presents a large impact on diagnosis and management of patients with lesions from blunt abdominal traumas. It is important to establish a prognostic criteria allowing decisions for conservative or surgical treatment; CT findings

Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

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Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

2014-05-01

Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

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Anders, Lisanne C [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Cave, Matt [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); Arteel, Gavin E [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); McClain, Craig J [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); and others

2016-11-15

Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

International Nuclear Information System (INIS)

Anders, Lisanne C; Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N; Cave, Matt; Arteel, Gavin E; McClain, Craig J

2016-01-01

Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE

Neuromuscular stimulation therapy after incomplete spinal cord injury promotes recovery of interlimb coordination during locomotion

Science.gov (United States)

Jung, R.; Belanger, A.; Kanchiku, T.; Fairchild, M.; Abbas, J. J.

2009-10-01

The mechanisms underlying the effects of neuromuscular electrical stimulation (NMES) induced repetitive limb movement therapy after incomplete spinal cord injury (iSCI) are unknown. This study establishes the capability of using therapeutic NMES in rodents with iSCI and evaluates its ability to promote recovery of interlimb control during locomotion. Ten adult female Long Evans rats received thoracic spinal contusion injuries (T9; 156 ± 9.52 Kdyne). 7 days post-recovery, 6/10 animals received NMES therapy for 15 min/day for 5 days, via electrodes implanted bilaterally into hip flexors and extensors. Six intact animals served as controls. Motor function was evaluated using the BBB locomotor scale for the first 6 days and on 14th day post-injury. 3D kinematic analysis of treadmill walking was performed on day 14 post-injury. Rodents receiving NMES therapy exhibited improved interlimb coordination in control of the hip joint, which was the specific NMES target. Symmetry indices improved significantly in the therapy group. Additionally, injured rodents receiving therapy more consistently displayed a high percentage of 1:1 coordinated steps, and more consistently achieved proper hindlimb touchdown timing. These results suggest that NMES techniques could provide an effective therapeutic tool for neuromotor treatment following iSCI.

Experimental Hepatic Carcinogenesis: Oxidative Stress and Natural Antioxidants

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Velid Unsal

2017-08-01

Full Text Available Hepatocellular carcinoma is one of the most common cancers in the world, and it is influenced by agents such as DEN, 2-AAF, phenobarbital, alcohol, aflatoxin B1 metabolite or hepatitis viruses (B and C. Oxidative stress is becoming recognized as a key factor in the progression of hepatocarcinogenesis. Reactive oxygen species can play a leading role in initiation and promotion of hepatic carcinogenesis. The metabolites of DEN Diethylnitrosamine (DEN mediate the binding of tumour promoters by covalently binding to the DNA with one or two oxidation-providing electrons. 2-AAF is the inducer of DEN, and it is involved in tumour formation in the bladder and liver. Reactive Oxygen species (ROS; carbohydrates, lipids, DNA and enzymes, such as affect all important structures. Additionally, an excessive amount of ROS is highly toxic to cells. Antioxidants are protects against ROS, toxic substances, carcinogens. This review focuses on the literature on studies of Hepatic Carcinogenesis, oxidative stress and antioxidant therapy.

NK1.1+ cells promote sustained tissue injury and inflammation after trauma with hemorrhagic shock.

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Chen, Shuhua; Hoffman, Rosemary A; Scott, Melanie; Manson, Joanna; Loughran, Patricia; Ramadan, Mostafa; Demetris, Anthony J; Billiar, Timothy R

2017-07-01

Various cell populations expressing NK1.1 contribute to innate host defense and systemic inflammatory responses, but their role in hemorrhagic shock and trauma remains uncertain. NK1.1 + cells were depleted by i.p. administration of anti-NK1.1 (or isotype control) on two consecutive days, followed by hemorrhagic shock with resuscitation and peripheral tissue trauma (HS/T). The plasma levels of IL-6, MCP-1, alanine transaminase (ALT), and aspartate aminotransferase (AST) were measured at 6 and 24 h. Histology in liver and gut were examined at 6 and 24 h. The number of NK cells, NKT cells, neutrophils, and macrophages in liver, as well as intracellular staining for TNF-α, IFN-γ, and MCP-1 in liver cell populations were determined by flow cytometry. Control mice subjected to HS/T exhibited end organ damage manifested by marked increases in circulating ALT, AST, and MCP-1 levels, as well as histologic evidence of hepatic necrosis and gut injury. Although NK1.1 + cell-depleted mice exhibited a similar degree of organ damage as nondepleted animals at 6 h, NK1.1 + cell depletion resulted in marked suppression of both liver and gut injury by 24 h after HS/T. These findings indicate that NK1.1 + cells contribute to the persistence of inflammation leading to end organ damage in the liver and gut. © Society for Leukocyte Biology.

Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids

NARCIS (Netherlands)

Marsman, H. A.; de Graaf, W.; Heger, M.; van Golen, R. F.; ten Kate, F. J. W.; Bennink, R.; van Gulik, T. M.

2013-01-01

Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. Steatosis was induced in rats by a 3-week

Resveratrol Promotes Nerve Regeneration via Activation of p300 Acetyltransferase-Mediated VEGF Signaling in a Rat Model of Sciatic Nerve Crush Injury.

Science.gov (United States)

Ding, Zhuofeng; Cao, Jiawei; Shen, Yu; Zou, Yu; Yang, Xin; Zhou, Wen; Guo, Qulian; Huang, Changsheng

2018-01-01

Peripheral nerve injuries are generally associated with incomplete restoration of motor function. The slow rate of nerve regeneration after injury may account for this. Although many benefits of resveratrol have been shown in the nervous system, it is not clear whether resveratrol could promote fast nerve regeneration and motor repair after peripheral nerve injury. This study showed that the motor deficits caused by sciatic nerve crush injury were alleviated by daily systematic resveratrol treatment within 10 days. Resveratrol increased the number of axons in the distal part of the injured nerve, indicating enhanced nerve regeneration. In the affected ventral spinal cord, resveratrol enhanced the expression of several vascular endothelial growth factor family proteins (VEGFs) and increased the phosphorylation of p300 through Akt signaling, indicating activation of p300 acetyltransferase. Inactivation of p300 acetyltransferase reversed the resveratrol-induced expression of VEGFs and motor repair in rats that had undergone sciatic nerve crush injury. The above results indicated that daily systematic resveratrol treatment promoted nerve regeneration and led to rapid motor repair. Resveratrol activated p300 acetyltransferase-mediated VEGF signaling in the affected ventral spinal cord, which may have thus contributed to the acceleration of nerve regeneration and motor repair.

Extreme' vasculobiliary injuries: association with fundus-down cholecystectomy in severely inflamed gallbladders

NARCIS (Netherlands)

Strasberg, Steven M.; Gouma, Dirk J.

2012-01-01

Objectives: Extreme vasculobiliary injuries usually involve major hepatic arteries and portal veins. They are rare, but have severe consequences, including rapid infarction of the liver. The pathogenesis of these injuries is not well understood. The purpose of this study was to elucidate the

Quercetin promotes proliferation and differentiation of oligodendrocyte precursor cells after oxygen/glucose deprivation-induced injury.

Science.gov (United States)

Wu, Xiuxiang; Qu, Xuebin; Zhang, Qiang; Dong, Fuxing; Yu, Hongli; Yan, Chen; Qi, Dashi; Wang, Meng; Liu, Xuan; Yao, Ruiqin

2014-04-01

The aim of this study was to investigate quercetin's (Qu) ability to promote proliferation and differentiation of oligodendrocyte precursor cells (OPCs) under oxygen/glucose deprivation (OGD)-induced injury in vitro. The results showed that after OGD, OPCs survival rate was significantly increased by Qu as measured by Cell Counting Kit-8. Furthermore, Qu treatment reduced apoptosis of OPCs surveyed by Hoechst 33258 nuclear staining. Qu at 9 and 27 μM promoted the proliferation of OPCs the most by Brdu and Olig2 immunocytochemical staining after OGD 3 days. Also, Qu treatment for 8 days after OGD, the differentiation of OPCs to oligodendrocyte was detected by immunofluorescence staining showing that O4, Olig2, and myelin basic protein (MBP) positive cells were significantly increased compared to control group. Additionally, the protein levels of Olig2 and MBP of OPCs were quantified using western blot and mRNA levels of Olig2 and Inhibitor of DNA binding 2 (Id2) were measured by RT-PCR. Western blot showed a significant increase in Olig2 and MBP expression levels compared with controls after OGD and Qu treatment with a linear does-response curve from 3 to 81 μM. After treatment with Qu compared to its control group, Olig2 mRNA level was significantly up-regulated, whereas Id2 mRNA level was down-regulated. In conclusion, Qu at 3-27 μM can promote the proliferation and differentiation of OPCs after OGD injury and may regulate the activity of Olig2 and Id2.

Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation

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Yanli Li

2016-09-01

Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFAs exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A was administered intravenously to wild-type (WT and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ. In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

Epidemiological evaluation of hepatic trauma victims undergoing surgery.

Science.gov (United States)

Kalil, Mitre; Amaral, Isaac Massaud Amim

2016-02-01

to evaluate the epidemiological variables and diagnostic and therapeutic modalities related to hepatic trauma patients undergoing laparotomy in a public referral hospital in the metropolitan region of Vitória-ES. we conducted a retrospective study, reviewing charts of trauma patients with liver injuries, whether isolated or in association with other organs, who underwent exploratory laparotomy, from January 2011 to December 2013. We studied 392 patients, 107 of these with liver injury. The male: female ratio was 6.6 : 1 and the mean age was 30.12 years. Penetrating liver trauma occurred in 78.5% of patients, mostly with firearms. Associated injuries occurred in 86% of cases and intra-abdominal injuries were more common in penetrating trauma (p trauma was 60%, and penetrating trauma, 87.5% (p trauma remain high, especially in patients suffering from blunt trauma in relation to penetrating one.

Spontaneous and traumatic hepatic rupture: imaging findings and minimally invasive treatment

International Nuclear Information System (INIS)

Palacio, Glaucia Andrade e Silva; D'Ippolito, Giuseppe

2003-01-01

Spontaneous hepatic bleeding is a rare condition. Our aim was to describe the imaging findings and minimally invasive treatment using transcatheter arterial embolization in patients with spontaneous and traumatic hepatic rupture. Three patients presented acute hemoperitoneum dur to hepatic rupture caused by spontaneous rupture of hepatocellular carcinoma, HELLP syndrome and a blunt hepatic trauma. The patients were submitted to ultrasound and computed tomography of the abdomen and subsequently treated by transcatheter arterial embolization. All patients underwent helical computed tomography before and after treatments. Computed tomography played an important role in the evaluation and follow-up in the therapeutic intervention. Different types of liver injuries were identified. Transcatheter arterial embolization blocked arterial hemorrhage in the patients who were hemodynamically unstable. The conclusion was: transcatheter arterial embolization is an effective and well-tolerated treatment method for the management of hepatic rupture and computed tomography is an excellent method for the diagnosis and follow-up of these patients. (author)

Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis.

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Mehta, Minal B; Shewale, Swapnil V; Sequeira, Raymond N; Millar, John S; Hand, Nicholas J; Rader, Daniel J

2017-06-23

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G L ) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion ( Ppp1r3b Δ hep ) or liver-specific overexpression of Ppp1r3b The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3b Δ hep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3b Δ hep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

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Tomishima Yoshiro

2013-01-01

Full Text Available Abstract Background Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2 synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg. The effects of ozagrel (200 mg/kg treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL on cytochrome P450 2E1 (CYP2E1 activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM were evaluated by the WST-1 cell viability assay. Results Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos and C/EBP homologous protein (chop, but did not suppress B-cell lymphoma 2-like protein11 (bim expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest

Electrical Stimulation of Motor Cortex in the Uninjured Hemisphere after Chronic Unilateral Injury Promotes Recovery of Skilled Locomotion through Ipsilateral Control

OpenAIRE

Carmel, Jason B.; Kimura, Hiroki; Martin, John H.

2014-01-01

Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To ...

Blunt abdominal trauma in adults: role of CT in the diagnosis and management of visceral injuries. Part 1. Liver and spleen

Energy Technology Data Exchange (ETDEWEB)

Becker, C.D.; Terrier, F. [Department of Radiology, Division of Diagnostic and Interventional Radiology, Geneva University Hospital, Geneva (Switzerland); Mentha, G. [Department of Surgery, Division of Abdominal Surgery, Geneva University Hospital, Geneva (Switzerland)

1998-05-01

Computed tomography is now widely used in the initial diagnostic workup of adult trauma victims with suspected intra-abdominal injuries. We review the role of CT in the detection and management of blunt visceral injuries in two parts. In the first part we discuss general aspects of performing CT in the setting of abdominal trauma and the diagnostic findings of intra-abdominal hemorrhage and blunt hepatic and splenic injuries. Hepatic and splenic injuries can be detected by means of CT with a high accuracy. The vast majority of hepatic injuries can be successfully managed conservatively, even when CT demonstrates parenchymal damage of more than three segments and major hemoperitoneum. Delayed complications, e. g., formation of biloma or a false aneurysm, can be readily detected on repeat CT studies, although they are quite uncommon. The outcome of conservative treatment of splenic injuries remains unpredictable because delayed splenic rupture may occur even when initial CT shows only minor parenchymal lesions and little or no intraperitoneal hemorrhage. (orig.) With 11 figs., 5 tabs., 64 refs.

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis.

Science.gov (United States)

Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi; Phillips, Naomi G; Sonntag, Tim; Hao, Ergeng; Lee, Soon; Hai, Tsonwin; Montminy, Marc

2015-03-03

Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways.

Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

Science.gov (United States)

Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

2018-06-01

As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Tributyltin promoted hepatic steatosis in zebrafish (Danio rerio) and the molecular pathogenesis involved.

Science.gov (United States)

Zhang, Jiliang; Sun, Ping; Kong, Tao; Yang, Fan; Guan, Wenchao

2016-01-01

Endocrine disruptor effects of tributyltin (TBT) are well established in fish. However, the adverse effects on lipid metabolism are less well understood. Since the liver is the predominant site of de novo synthesis of lipids, the present study uses zebrafish (Danio rerio) to examine lipid accumulation in the livers and hepatic gene expression associated with lipid metabolism pathways. After exposure for 90 days, we found that the livers in fish exposed to TBT were yellowish in appearance and with accumulation of lipid droplet, which is consistent with the specific pathological features of steatosis. Molecular analysis revealed that TBT induced hepatic steatosis by increasing the gene expression associated with lipid transport, lipid storage, lipiogenic enzymes and lipiogenic factors in the livers. Moreover, TBT enhanced hepatic caspase-3 activity and up-regulated genes related to apoptosis and cell-death, which indicated steatotic livers of fish exposed to TBT and the subsequent liver damage were likely due to accelerated hepatocyte apoptosis or cell stress. In short, TBT can produce multiple and complex alterations in transcriptional activity of lipid metabolism and cell damage, which provides potential molecular evidence of TBT on hepatic steatosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Percutaneous injection of hemostatic agents for severe blunt hepatic trauma: an experimental study

International Nuclear Information System (INIS)

Tang, Jie; Lv, Faqin; Li, Wenxiu; Zhang, Huiqin; Luo, Yukun; An, Lichun; Li, Tanshi

2008-01-01

This study was designed to evaluate whether percutaneous injection of hemostatic agents under the guidance of contrast-enhanced ultrasound (CEUS) can stop hemorrhage from severe hepatic trauma. Eighteen dogs were impacted by a miniature impactor to create blunt hepatic trauma. Fourteen with appropriate liver lesions were divided into two groups: the treatment group (n=7) and the control group (n=7). In the treatment group, hemocoagulase atrox and α-cyanoacrylate were respectively injected into the injury sites and transected micro-vessels under the guidance of CEUS. In the control group, normal saline was injected into the injury sites. CEUS and CT were performed at 3, 7, 14, and 21 days after the focal injection. Surviving animals were killed on the 21st day for pathologic examination. All animals of the treatment group survived. Three dogs of the control group died in the first 24 h. In the treatment group, CEUS and CT demonstrated that hepatic lesions became smaller gradually from the 3rd to the 21st day after injection. The focal injection of hemostatic agents under the guidance of CEUS can stop hemorrhage from hepatic trauma of grade III∝IV or IV. During the period of 3 weeks, no side effect was found. (orig.)

Percutaneous injection of hemostatic agents for severe blunt hepatic trauma: an experimental study

Energy Technology Data Exchange (ETDEWEB)

Tang, Jie; Lv, Faqin; Li, Wenxiu; Zhang, Huiqin; Luo, Yukun; An, Lichun [Chinese People' s Liberation Army General Hospital, Department of Ultrasound, Beijing (China); Li, Tanshi [Chinese People' s Liberation Army General Hospital, Department of Intensive Care Unit, Beijing (China)

2008-12-15

This study was designed to evaluate whether percutaneous injection of hemostatic agents under the guidance of contrast-enhanced ultrasound (CEUS) can stop hemorrhage from severe hepatic trauma. Eighteen dogs were impacted by a miniature impactor to create blunt hepatic trauma. Fourteen with appropriate liver lesions were divided into two groups: the treatment group (n=7) and the control group (n=7). In the treatment group, hemocoagulase atrox and {alpha}-cyanoacrylate were respectively injected into the injury sites and transected micro-vessels under the guidance of CEUS. In the control group, normal saline was injected into the injury sites. CEUS and CT were performed at 3, 7, 14, and 21 days after the focal injection. Surviving animals were killed on the 21st day for pathologic examination. All animals of the treatment group survived. Three dogs of the control group died in the first 24 h. In the treatment group, CEUS and CT demonstrated that hepatic lesions became smaller gradually from the 3rd to the 21st day after injection. The focal injection of hemostatic agents under the guidance of CEUS can stop hemorrhage from hepatic trauma of grade III{proportional_to}IV or IV. During the period of 3 weeks, no side effect was found. (orig.)

Assessment of hepatitis B vaccination status in doctors of Services hospital, Lahore

International Nuclear Information System (INIS)

Usmani, R.A.; Rana, M.S.; Sarwer, H.; Fazli, H.; Ali Pervaiz, M.A.; Tahir, I.; Sajjad, R.; Muhammad Saleem Wazir, M.S.

2010-01-01

Background: Hepatitis B is the most common serious infection of the liver and can lead to premature death from liver cancer or liver failure. Of the two billion people who have been infected with Hepatitis B virus, more than 350 million have chronic infection. The objectives of this study were to assess the Hepatitis B vaccination status, reasons for non-compliance and the risk of exposure to doctors at a tertiary care hospital. Methods: Three hundred and twenty-two doctors were selected from the various departments of the hospital by simple random sampling. They were given a self-administered questionnaire after taking verbal consent. Some doctors refused to fill-in the questionnaire while some others were on leave during the time of study and the remaining 215 doctors responded to the questionnaire. Results: A total of 215 doctors, (age range 22-59 years) responded to the questionnaire. Amongst them 11.6% had not received even a single dose of Hepatitis B vaccine while 14.4% had not completed the required course of vaccination. Most common reason cited by doctors for non immunisation was that they had not thought about it. Consultants were more likely of the other doctors to have received completed vaccination (83.9% versus 69.9%) (p<0.05). They were also significantly more likely to know their antibody titre after completing vaccination. Needle stick injuries were common. One hundred and forty-five doctors in the study admitted having received at least one needle prick/sharp injury. Of them, 51.6% had received a needle prick/sharp injury more than once. Conclusion: Despite the availability of an effective vaccine in the market doctors continue to remain non-vaccinated. It is the lack of awareness and carelessness on part of doctors coupled with the negligence of the risk that has led them being incompletely vaccinated. There is a need to ensure that every doctor is completely vaccinated against Hepatitis B before he/she enters professional practice. (author)

Radioprotective effect of hematopoietic growth factor gene therapy regulated by Egr-1 promoter on radiation injury of SCID mice

International Nuclear Information System (INIS)

Du Nan; Pei Xuetao; Luo Chengji; Su Yongping; Cheng Tianmin

2002-01-01

Objective: To explore the radioprotective effect of the expression of hematopoietic growth factors regulated by radio-inducible promoter on radiation injury. Methods: The human FL cDNA and EGFP cDNA were linked together with an internal ribosome entry site (IRES) and then inserted into the eukaryotic expression vector pCI-neo with the Egr-1 promoter (Egr-EF), and further transduced into bone marrow stromal cell lines HFCL (HFCL/EF). The HFCL/EF and CD34 + cells from human umbilical cord blood were transplanted i.v. one after the other into sublethally irradiated severe combined immunodeficient (SCID) mice. The number of peripheral blood WBC and human cells engrafted in recipient mice were detected by flow cytometry and CFU-GM assay. Results: In contrast to two control groups (HFCL and HFCL/F), HFCL/EF (the Egr-1 regulatory element-driven expression of FL gene therapy) resulted in a proportionally obvious increase in the number of the WBC at early stage after irradiation. Significant differences were found for CD45 + , CD34 + , CFU-GM, and nucleated cells in the bone marrow. Conclusion: Hematopoietic growth factor gene therapy regulated by radio-inducible promoter has radioprotective effect on radiation hematopoietic injury

Injuries of the retrohepatic inferior vena cava and the liver

Directory of Open Access Journals (Sweden)

Koprivica Radenko

2008-01-01

Full Text Available Beckground. Injuries of the retrohepatic inferior vena cava, and the liver have mortality rate up to 71-78%. We presented a patient with combined injury of the retrohepatic inferior vena cava, liver, craniocerebral and thoracic traumas, inflicted in a traffic accident. Case report. Man, 20 years old has been injured in a traffic accident. At admission, 20 minutes after the injury, the patient was comatose and hypotensive. Bloody content was obtained by abdominal tracer. The patient underwent emergent laparotomy, utilizing trifurcated incision and cell saver device. Abdominal exploration revealed two liters of free blood and massive retroperitoneal hematoma. Manual compression of the liver was done, as well as perihepatic packing, complete hepatic vascular exclusion and mobilization of the right liver lobe. Due to impressive chemodynamic instability supraceliac aortic clamping was performed. Upon exposure of the retrohepatic inferior vena cava and right liver lobe, multiple lacerations of retrohepatic inferior vena cava and right hepatic vein, and right hepatic vein avulsion were found. We also identified an injury of VII and VIII segments of the liver (grade V according to the Moore's classification. Nonexpansive hepatoduodenal ligament hematoma and the injury of II and III segments of the liver group II/III according to Moore were found. Venorrhaphy of the inferior vena cava was done in the area of circumference of the right hepatic vein, a portion of which served as autologous vein patch. Continuous prolene 3/0 venorrhaphy of the distal caval laceration was done. Total caval and aorta clamping time of the inferior vena cava was 41 minutes. Atypical resection, debridment, of hepatic segments was done by using a harmonic scalpel. Hepatoduodenal ligament was declamped after 65 minutes. Fibrin glue was applied on the resectioned area of liver. The patient received 3.2 l of autologuos blood transfusion with 5 units of packed red blood cells, 6