Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

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Zan, Yanlu [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Zhang, Yuxia, E-mail: yzhang@wehi.edu.au [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Tien, Po, E-mail: tienpo@sun.im.ac.cn [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China)

2013-06-07

Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs.

PPARα ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats

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Toyama, Tetsuya; Nakamura, Hideki; Harano, Yuichi; Yamauchi, Norihito; Morita, Atsuhiro; Kirishima, Toshihiko; Minami, Masahito; Itoh, Yoshito; Okanoue, Takeshi

2004-01-01

Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor which is known to affect oxidative stress and PPARα ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARα ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA + WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARα ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver

Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats.

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Vilaseca, Marina; García-Calderó, Héctor; Lafoz, Erica; Ruart, Maria; López-Sanjurjo, Cristina Isabel; Murphy, Michael P; Deulofeu, Ramon; Bosch, Jaume; Hernández-Gea, Virginia; Gracia-Sancho, Jordi; García-Pagán, Juan Carlos

2017-07-01

In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension. Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl 4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation. Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl 4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model. We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Vitamin B12 supplement alleviates N'-nitrosodimethylamine-induced hepatic fibrosis in rats.

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Ahmad, Areeba; Afroz, Nishat; Gupta, Umesh D; Ahmad, Riaz

2014-01-10

Abstract Context: Altered vitamin B 12 levels have been correlated with hepatotoxicity; however, further evidence is required to establish its protective role. Objective: To evaluate the effects of vitamin B 12 supplement in protecting N'-nitrosodimethylamine (NDMA)-induced hepatic fibrosis in Wistar rats. Materials and methods: Hepatic fibrosis was induced by administering NDMA in doses of 10 mg/kg body weight thrice a week for 21 days. Another group received equal doses (10 mg/kg body weight) of vitamin B 12 subsequent to NDMA treatment. Animals from either group were sacrificed weekly from the start of the treatment along with their respective controls. Progression of hepatic fibrosis, in addition to the effect of vitamin B 12 , was assessed biochemically for liver function biomarkers, liver glycogen, hydroxyproline (HP) and B 12 reserves along with histopathologically by hematoxylin and eosin (H & E) as well immunohistochemical staining for α-SMA expression. Results and discussion: Elevation in the levels of aminotransferases, SALP, total bilirubin and HP was observed in NDMA treated rats, which was concomitant with remarkable depletion in liver glycogen and B 12 reserves (p < 0.05). Liver biopsies also demonstrated disrupted lobular architecture, collagen amassing and intense fibrosis by NDMA treatment. Immunohistochemical staining showed the presence of activated stellate cells that was dramatically increased up to day 21 in fibrotic rats. Following vitamin B 12 treatment, liver function biomarkers, glycogen contents and hepatic vitamin B 12 reserves were restored in fibrotic rats, significantly. Vitamin B 12 administration also facilitated restoration of normal liver architecture. Conclusion: These findings provide interesting new evidence in favor of protective role for vitamin B 12 against NDMA-induced hepatic fibrosis in rats.

An iron-deficient diet stimulates the onset of the hepatitis due to hepatic copper deposition in the Long-Evans Cinnamon (LEC) rat

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Sugawara, Naoki; Sugawara, Chieko [Sapporo Medical Univ. (Japan). Dept. of Public Health

1999-09-01

To study effects of dietary Cu and Fe levels on the onset of hepatitis in Long-Evans Cinnamon (LEC) rats, female rats (40 days old) were fed a semipurified diet containing 0.1 or 10 mg Cu/kg and 1.5 or 150 mg Fe/kg in a 2 x 2 factorial arrangement for 35 days. At 75 days after birth, LEC rats (+Cu-Fe) fed a Cu-sufficient but Fe-deficient diet (Cu, 10 mg/kg; Fe, 1.5 mg/kg) showed jaundice, with lethargy, anorexia, and malaise. The biochemical variables relating to liver function were significantly increased compared to three other groups, a Cu- and Fe-deficient (-Cu-Fe) group, a Cu-deficient but Fe-sufficient (-Cu+Fe) group, and a Cu and Fe sufficient (+Cu+Fe) group. Furthermore, the +Cu-Fe rat liver showed massive necrosis with huge nuclei. The other three groups presented no biochemical and histological findings of hepatitis. Hepatic Cu and metallothionein concentrations were 289 {+-} 87 (mean {+-} SD) {mu}g/g liver and 8.7 {+-} 1.8 mg/g liver, respectively, in the +Cu-Fe rats. However, in the +Cu+Fe group the values were 196 {+-} 28 {mu}g Cu/g liver and 10.8 {+-} 1.0 mg/g liver. Hepatic Fe deposition was not influenced significantly by the dietary Cu level. The +Cu-Fe group with jaundice showed the highest free Cu concentration in the liver among the four groups, but the hepatic free Fe concentration was similar to those in the -Cu+Fe and +Cu+Fe groups. Our results indicate that an Fe-deficient diet enhances the deposition of hepatic Cu due to increased absorption of Cu from the gastrointestinal tract. This deposition stimulated the onset of hepatitis. (orig.)

Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

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Frantz, Eliete Dalla Corte; Medeiros, Renata Frauches; Giori, Isabele Gomes; Lima, Juliana Bittencourt Silveira; Bento-Bernardes, Thais; Gaique, Thaiane Gadioli; Fernandes-Santos, Caroline; Fernandes, Tiago; Oliveira, Edilamar Menezes; Vieira, Carla Paulo; Conte-Junior, Carlos Adam; Oliveira, Karen Jesus; Nobrega, Antonio Claudio Lucas

2017-09-01

What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l -1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day -1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and

Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats.

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Feng, Wenhuan; Wang, Hongdong; Zhang, Pengzi; Gao, Caixia; Tao, Junxian; Ge, Zhijuan; Zhu, Dalong; Bi, Yan

2017-07-01

Structural disruption of gut microbiota contributes to the development of non-alcoholic fatty liver disease (NAFLD) and modulating the gut microbiota represents a novel strategy for NAFLD prevention. Although previous studies have demonstrated that curcumin alleviates hepatic steatosis, its effect on the gut microbiota modulation has not been investigated. Next generation sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota in a NAFLD rat model induced by high fat-diet (HFD) feeding. We found that curcumin attenuated hepatic ectopic fat deposition, improved intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD-fed rats. More importantly, curcumin dramatically shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean rats fed a normal diet and altered the gut microbial composition. The abundances of 110 operational taxonomic units (OTUs) were altered by curcumin. Seventy-six altered OTUs were significantly correlated with one or more hepatic steatosis associated parameters and designated 'functionally relevant phylotypes'. Thirty-six of the 47 functionally relevant OTUs that were positively correlated with hepatic steatosis associated parameters were reduced by curcumin. These results indicate that curcumin alleviates hepatic steatosis in part through stain-specific impacts on hepatic steatosis associated phylotypes of gut microbiota in rats. Compounds with antimicrobial activities should be further investigated as novel adjunctive therapies for NAFLD. Copyright © 2017 Elsevier B.V. All rights reserved.

Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats.

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Morán-Ramos, Sofía; Avila-Nava, Azalia; Tovar, Armando R; Pedraza-Chaverri, José; López-Romero, Patricia; Torres, Nimbe

2012-11-01

Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had ∼50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats.

Increased hepatic glycogen synthetase and decreased phosphorylase in trained rats

DEFF Research Database (Denmark)

Galbo, H; Saugmann, P; Richter, Erik

1979-01-01

Rats were either physically trained by a 12 wk swimming program or were freely eating or weight matched, sedentary controls. Trained rats had a higher relative liver weight and total hepatic glycogen synthetase (EC 2.4.1.11) activity and a lower phosphorylase (EC 2.4.1.1) activity than the other...

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.

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.

DDT increases hepatic testosterone metabolism in rats

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Sierra-Santoyo, Adolfo; Albores, Arnulfo; Cebrian, Mariano E. [Cinvestav-IPN, Seccion de Toxicologia, Mexico (Mexico); Hernandez, Manuel [Cinvestav-IPN, Departamento de Biologia Celular (Mexico)

2005-01-01

DDT and its metabolites are considered as endocrine disruptors able to promote hormone-dependent pathologies. We studied the effects of technical-grade DDT on hepatic testosterone metabolism and testosterone hydroxylase activity ratios in the rat. Male and female Wistar rats were treated by gavage with a single dose of technical-grade DDT (0, 0.1, 1, 10, and 100 mg/kg body weight) and killed 24 h later. Hepatic microsomes were incubated with [4-{sup 14}C]-testosterone and the metabolites were separated by thin-layer chromatography and quantified by radio scanning. DDT increased testosterone biotransformation and modified the profile of metabolites produced in a sex-dependent manner. Males treated with a representative dose (10 mg/kg) produced relatively less androstenedione (AD), 2{alpha}-hydroxytestosterone (OHT), and 16{alpha}-OHT but higher 6{beta}-OHT whereas treated females produced less 7{alpha}-OHT and AD but higher 6{beta}-OHT and 6{alpha}-OHT than their respective controls. In both sexes DDT decreased the relative proportion of AD and increased that of 6{beta}-OHT suggesting that the androgen-saving pathway was affected. The testosterone 6{alpha}-/15{alpha}-OHT ratio, a proposed indicator of demasculinization, was increased in treated males. This effect was in agreement with the demasculinizing ability proposed for DDT. The effects on 6{alpha}-/16{alpha}-OHT and 6-dehydrotestosterone/16{alpha}-OHT ratios followed a similar tendency, with the ratio 6{alpha}-/16{alpha}-OHT being the most sensitive marker. Interestingly, these ratios were reduced in treated females suggesting that technical-grade DDT shifted testosterone hydroxylations toward a more masculine pattern. Thus, technical-grade DDT altered the hepatic sexual dimorphism in testosterone metabolism and decreased the metabolic differences between male and female rats. (orig.)

Increased hepatic nicotine elimination after phenobarbital induction in the conscious rat

International Nuclear Information System (INIS)

Foth, H.; Walther, U.I.; Kahl, G.F.

1990-01-01

Elimination parameters of [14C]nicotine in conscious rats receiving nicotine (0.3 mg/kg) either intravenously or orally were studied. The oral availability of unchanged nicotine, derived by comparison of the respective areas under the concentration vs time curves (AUC), was 89%, indicating low hepatic extraction ratios of about 10%. Pretreatment of rats with phenobarbital (PB) markedly increased hepatic first-pass extraction of nicotine. The oral availability of unchanged nicotine in plasma dropped to 1.4% of the corresponding values obtained from PB-treated rats receiving nicotine iv. After PB pretreatment, the clearance of iv nicotine was increased approximately twofold over controls, much less than the observed more than ninefold increase of hepatic first-pass extraction. It is assumed that extrahepatic metabolism contributed significantly to the rapid removal of nicotine from the plasma. The elimination of cotinine, originating from nicotine administered either po or iv, was significantly increased by PB pretreatment, as determined by the ratio of corresponding AUCs. The pattern of nicotine metabolites in urine also indicated an increase in the rate of cotinine metabolic turnover. The amount of norcotinine in the organic extract of urine paralleled PB microsomal enzyme induction. The ratio between urinary concentrations of the normetabolite and cotinine correlated strongly with the PB-induced state of rat liver. This may be a suitable indicator of PB-inducible hepatic cytochrome P450 isoenzyme(s). Since smoking habits in man are feedback-regulated by nicotine plasma concentrations, a similar increase of nicotine elimination by microsomal enzyme induction in man may be of relevance for tobacco consumption

Exercise and Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Hepatic Steatosis in Hyperphagic OLETF Rats

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Sarah J. Borengasser

2012-01-01

Full Text Available Background and Aims. This study examined if exercise and omega-3 fatty acid (n3PUFA supplementation is an effective treatment for hepatic steatosis in obese, hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF rats. Methods. Male OLETF rats were divided into 4 groups (n=8/group: (1 remained sedentary (SED, (2 access to running wheels; (EX (3 a diet supplemented with 3% of energy from fish oil (n3PUFA-SED; and (4 n3PUFA supplementation plus EX (n3PUFA+EX. The 8 week treatments began at 13 weeks, when hepatic steatosis is present in OLETF-SED rats. Results. EX alone lowered hepatic triglyceride (TAG while, in contrast, n3PUFAs failed to lower hepatic TAG and blunted the ability of EX to decrease hepatic TAG levels in n3PUFAs+EX. Insulin sensitivity was improved in EX animals, to a lesser extent in n3PUFA+EX rats, and did not differ between n3PUFA-SED and SED rats. Only the EX group displayed higher complete hepatic fatty acid oxidation (FAO to CO2 and carnitine palmitoyl transferase-1 activity. EX also lowered hepatic fatty acid synthase protein while both EX and n3PUFA+EX decreased stearoyl CoA desaturase-1 protein. Conclusions. Exercise lowers hepatic steatosis through increased complete hepatic FAO, insulin sensitivity, and reduced expression of de novo fatty acid synthesis proteins while n3PUFAs had no effect.

Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats.

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Mao Li

Full Text Available Non-alcoholic fatty liver disease (NAFLD caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated.This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators.SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG, insulin, triglyceride (TG, total cholesterol (TC, low-density lipoprotein cholesterol (LDL-C, high-density lipoprotein cholesterol (HDL-C and free fatty acid (FFA levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA.The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention.Octreotide can ameliorate hepatic steatosis in obese rats

Gastro Hepatic Protective Effects of Sildenafil in γ-Irradiated Rats

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Tawfik, S.S.; Salama, S.F.

2013-01-01

Sildenafil is a potent specific inhibitor of phosphodiesterase-5 (PDE-5), which ultimately increases intracellular cyclic guanosine monophosphate (cGMP) . Sildenafil commercially named Viagra; was studied for its gastro hepatic protective activity through acute exposure of rats to γ-rays. The experimental groups of rats were: Sildenafil [1 mg/ kg, intra venous (i.v.), in 0.2 ml saline] / day for 5 days and then exposed to 6 Gy γ-rays after 1 h of the last injection (sildenafil+ γ-rays group). Controls received saline as a vehicle/ for 5 day; sildenafil group received drug alone for 5 days, and γ-rays group received saline (without drug) for 5 days and exposed to 6 Gy γ-rays after 1 h of the last injection. All groups were decapitated on the 6th day. Gamma rays increased the level of malondialdehyde (MDA) and the activity of myeloperoxidase (MPO) but, lowered the levels of nitric oxide (NO) and reduced glutathione (GSH) as well as lowering the activities of superoxide dismutase (SOD) and catalase (CAT) in both stomach and hepatic tissues. Sildenafil administrated before γ-rays significantly reduced the level of MDA and the activity of MPO while elevating levels of NO and GSH plus activities of SOD and CAT in both stomach and hepatic tissues compared to control and sildenafil groups. Conclusion: The data reveals that sildenafil pre-treatment has a protective effect against γ-rays-induced gastro hepatic dysfunction and supports the possible use of sildenafil as a protective agent in γ-irradiated rats

Accretion of visceral fat and hepatic insulin resistance in pregnant rats.

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Einstein, Francine H; Fishman, Sigal; Muzumdar, Radhika H; Yang, Xiao Man; Atzmon, Gil; Barzilai, Nir

2008-02-01

Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF-; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 +/- 0.3, Preg 10.0 +/- 1.0 g, P Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg.kg(-1).min(-1)) was highest in Nonpreg (19.4 +/- 2.0), lowest in Preg (11.1 +/- 1.4), and intermediate in PVF- (14.7 +/- 0.6; P insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 +/- 1.3, Preg 9.3 +/- 0.5 mg.kg(-1).min(-1); P insulin sensitivity was similar to nonpregnant levels in PVF- (HGP 4.9 +/- 0.8 mg.kg(-1).min(-1)). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 +/- 0.4 vs. Preg 3.2 +/- 0.3 mg/g) and decreased with removal of VF (PVF- 1.3 +/- 0.4 mg/g; P insulin action in pregnancy.

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.

Comparison of hepatic fibrosis models and associated hepatic fibronectin expression in Wistar rats treated by bile duct ligation and CCl4

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LIU Xiaoya

2015-02-01

Full Text Available ObjectiveTo compare serum biochemical parameters, liver pathology, and fibronectin (FN expression in Wister rats with hepatic fibrosis induced by bile duct ligation (BDL and carbon tetrachloride (CCl4. MethodsNinety healthy male Wister rats were assigned to CCl4 model (n=44, CCl4 control (n=6, BDL model (n=30, and BDL control groups (n=10. Animal models of hepatic fibrosis were established by intraperitoneal injection of olive oil solution containing 50% CCl4 in the CCl4 model group and by BDL in the BDL group. General conditions of rats were examined. Expression of serum alanine aminotransferase (ALT, serum aspartate aminotransferase (AST, total bilirubin (TBil, and direct bilirubin (DBil was measured by biochemical analysis. Expression of serum hyaluronic acid (HA and laminin (LN was measured by ELISA assay. Pathological changes in liver tissue were examined through hematoxylin-eosin and Masson staining. Expression of FN was assayed by immunohistochemistry. Comparison between groups was made by t test. ResultsSerum biochemical analysis showed that TBil and DBil levels in BDL model rats increased to and maintained at relatively high levels from day 7 after surgery (P<0.05; these two parameters in CCl4 model rats increased gradually from week 2 and peaked at week 8 after injection (P<0.05. The indicators of hepatic fibrosis, i.e., HA and LN levels, were significantly higher in the BDL model group than in the CCl4 model group. Pathologically, the CCl4 model group showed diffuse fatty degeneration of liver cells, with extremely significant fiber interval formation in the portal area - portal area or the portal area - central vein; the BDL model group showed coexistence of significant intrahepatic bile duct hyperplasia, inflammatory cell infiltration, and fiber interval formation. In the BDL model group, FN expression was dispersive and irregular with thin fibrous tissues; in the CCl4 model group, FN was mostly expressed in the interlobular septa

Modified sleeve anastomosis for reconstruction of the hepatic artery in rat liver transplantation.

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Li, Jun; Dahmen, Uta; Dirsch, Olaf; Shen, Kai; Gu, Yanli; Broelsch, Christoph Erich

2002-01-01

End-to-end sleeve anastomosis between a donor common hepatic artery and a recipient proper hepatic artery was proven to be the most physiological and simple method for hepatic rearterialization in rat liver transplantation. Current technical variants of the sleeve technique, however, are hampered by the high rate of bleeding from the anastomotic site. This report deals with a technical modification which inhibits postoperative bleeding efficiently. The procedure consisted of a guiding suture, as previously described in other technical variants, and a modified fixing suture. Instead of using a single stitch to fix the feeding vessel with the receiving vessel, a running suture between the edge of the donor common hepatic artery and the adventitia of the recipient proper hepatic artery was performed to avoid a possible backflow. The patency rate of 91% was as high as reported by others using a sleeve technique, which was also reflected in the histomorphological picture, being indistinguishable from normal liver histology. This technical modification simplified the procedure of reconstructing the hepatic artery and could contribute to a wider use of the arterialized liver transplantation model in rats. Copyright 2002 Wiley-Liss, Inc.

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.

Science.gov (United States)

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.

The determination of hepatic blood flow in the rat using Xenon-133

International Nuclear Information System (INIS)

Smith, A.; Clarke, M.B.

1976-01-01

The measurement of hepatic blood flow in rats undergoing surgical trauma using different anaesthetic techniques has been carried out using the 133 Xe clearance method. Injection into the hepatic artery is followed by monitoring of the liver radioactivity. The complex clearance curves have been analysed using a computer. Details of the surgical technique and the care of the animal while undergoing examination are given. The physiological basis for the clearance curves observed is analysed and a survey of the various parameters which may produce changes in clearance rates is made. Comparison with other investigations show that rat liver blood flows obtained using the 133 Xe clearance method are consistent with others using non-radioactive techniques; because of its simplicity and ease of repetition, the Xenon method is recommended as a way of evaluating drug effects on hepatic blood flow in experimental animals. (author)

Impact of high altitude on the hepatic fatty acid oxidation and synthesis in rats

Energy Technology Data Exchange (ETDEWEB)

Ni, Qian [Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou (China); Department of Pediatrics, Lanzhou University Second Hospital, Lanzhou (China); Shao, Yuan; Wang, Ying Zhen [Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou (China); Jing, Yu Hong [Institute of Anatomy, School of Basic Medicine, Lanzhou University, Lanzhou (China); Zhang, You Cheng, E-mail: zhangychmd@126.com [Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou (China)

2014-04-04

Highlights: • Acute exposure to high altitude (HA) increased hepatic fatty acid (FA) β-oxidation. • Acute exposure of rats to HA increased hepatic FA synthesis. • PPARα and AMPK can regulate the FA metabolism. • FA may be a key energy fuel and a compensation for CHO during acute exposure to HA. • The acute changes of FA metabolism may be a mechanism of acclimatization. - Abstract: High altitude (HA) affects energy metabolism. The impact of acute and chronic HA acclimatization on the major metabolic pathways is still controversial. In this study, we aimed to unveil the impact of HA on the key enzymes involved in the fatty acid (FA) metabolism in liver. Rats were exposed to an altitude of 4300 m for 30 days and the expressions of two key proteins involved in FA β-oxidation (carnitine palmitoyl transferase I, CPT-I; and peroxisome proliferator-activated receptor alpha, PPARα), two proteins involved in FA synthesis (acetyl CoA carboxylase-1, ACC-1; and AMP-activated protein kinase, AMPK), as well as the total ketone body in the liver and the plasma FFAs were examined. Rats without HA exposure were used as controls. We observed that the acute exposure of rats to HA (3 days) led to a significant increase in the expressions of CPT-I and PPARα and in the total hepatic ketone body. Longer exposure (15 days) caused a marked decrease in the expression of CPT-I and PPARα. By 30 days after HA exposure, the expression levels of CPT-I and PPARα returned to the control level. The hepatic ACC-1 level showed a significant increase in rats exposed to HA for 1 and 3 days. In contrast, the hepatic level of AMPK showed a significant reduction throughout the experimental period. Plasma FFA concentrations did not show any significant changes following HA exposure. Thus, increased hepatic FA oxidation and synthesis in the early phase of HA exposure may be among the important mechanisms for the rats to respond to the hypoxic stress in order to acclimatize themselves to the

Impact of high altitude on the hepatic fatty acid oxidation and synthesis in rats

International Nuclear Information System (INIS)

Ni, Qian; Shao, Yuan; Wang, Ying Zhen; Jing, Yu Hong; Zhang, You Cheng

2014-01-01

Highlights: • Acute exposure to high altitude (HA) increased hepatic fatty acid (FA) β-oxidation. • Acute exposure of rats to HA increased hepatic FA synthesis. • PPARα and AMPK can regulate the FA metabolism. • FA may be a key energy fuel and a compensation for CHO during acute exposure to HA. • The acute changes of FA metabolism may be a mechanism of acclimatization. - Abstract: High altitude (HA) affects energy metabolism. The impact of acute and chronic HA acclimatization on the major metabolic pathways is still controversial. In this study, we aimed to unveil the impact of HA on the key enzymes involved in the fatty acid (FA) metabolism in liver. Rats were exposed to an altitude of 4300 m for 30 days and the expressions of two key proteins involved in FA β-oxidation (carnitine palmitoyl transferase I, CPT-I; and peroxisome proliferator-activated receptor alpha, PPARα), two proteins involved in FA synthesis (acetyl CoA carboxylase-1, ACC-1; and AMP-activated protein kinase, AMPK), as well as the total ketone body in the liver and the plasma FFAs were examined. Rats without HA exposure were used as controls. We observed that the acute exposure of rats to HA (3 days) led to a significant increase in the expressions of CPT-I and PPARα and in the total hepatic ketone body. Longer exposure (15 days) caused a marked decrease in the expression of CPT-I and PPARα. By 30 days after HA exposure, the expression levels of CPT-I and PPARα returned to the control level. The hepatic ACC-1 level showed a significant increase in rats exposed to HA for 1 and 3 days. In contrast, the hepatic level of AMPK showed a significant reduction throughout the experimental period. Plasma FFA concentrations did not show any significant changes following HA exposure. Thus, increased hepatic FA oxidation and synthesis in the early phase of HA exposure may be among the important mechanisms for the rats to respond to the hypoxic stress in order to acclimatize themselves to the

The relationship between plasma free fatty acids and experimentally induced hepatic encephalopathy in the rat

NARCIS (Netherlands)

Smit, J. J.; Bosman, D. K.; Jörning, G. G.; de Haan, J. G.; Maas, M. A.; Chamuleau, R. A.

1991-01-01

Two experimental models of hepatic encephalopathy in the rat have been investigated in order to study the postulated relationship between plasma free fatty acids concentration (C6 - C22:0) and the degree of hepatic encephalopathy. As a model of chronic hepatic encephalopathy, porta caval shunted

Dietary intake of ain-93 standard diet induces Fatty liver with altered hepatic fatty acid profile in Wistar rats.

Science.gov (United States)

Farias Santos, Juliana; Suruagy Amaral, Monique; Lima Oliveira, Suzana; Porto Barbosa, Júnia; Rego Cabral, Cyro; Sofia Melo, Ingrid; Bezerra Bueno, Nassib; Duarte Freitas, Johnatan; Goulart Sant'ana, Antônio; Rocha Ataíde, Terezinha

2015-05-01

There are several standard diets for animals used in scientific research, usually conceived by scientific institutions. The AIN-93 diet is widely used, but there are some reports of fatty liver in Wistar rats fed this diet. We aimed to evaluate the hepatic repercussions of the AIN-93 diet intake in Wistar rats. Forty newly-weaned 21-day-old male Wistar rats were fed either the AIN-93 diet or a commercial diet for either 1 month or 4 months. Weight gain, serum biochemistry, hepatic histology, and hepatic fatty acid profile were analyzed. Hepatic steatosis was observed, especially in the group fed the AIN-93 diet. Serum blood glucose, absolute and relative liver weight and hepatic levels of oleic, palmitoleic, stearic, and palmitic fatty acids were related to the observed steatosis, while lipidogram and serum markers of liver function and injury were not. AIN-93 diet induced acute hepatic steatosis in Wistar rats, which may compromise its use as a standard diet for experimental studies with rodents. The hepatic fatty acid profile was associated with steatosis, with possible implications for disease prognosis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

The regulatory effects of fish oil and chitosan on hepatic lipogenic signals in high-fat diet-induced obese rats.

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Chiu, Chen-Yuan; Chang, Tien-Chia; Liu, Shing-Hwa; Chiang, Meng-Tsan

2017-10-01

The present study investigated the regulatory effects of fish oil and chitosan on the signals of hepatic lipid metabolism and the postulated mechanism in high-fat diet-induced obese rats. Diet supplementation of chitosan and fish oil efficiently suppressed the increased weights in body and livers of high-fat diet-fed rats. Supplementation of chitosan and fish oil significantly decreased the activities of hepatic lipid biosynthesis-related enzymes and efficiently regulated plasma lipoprotein homeostasis. Both chitosan and fish oil significantly ameliorated the alterations in the protein expressions of hepatic lipogenic transcription factors (LXRα and PPARα), and could also significantly regulate the downstream hepatic lipogenic genes (FAS, HMGCR, CYP7A1, FATP, FABP, AOX, and ABCA) expressions in high-fat diet-fed rats. These results suggest that both fish oil and chitosan exerts downregulative effects on hepatic lipid metabolism in high-fat diet-induced obese rats via the LXRα inhibition and PPARα activation, which further affect the expressions of hepatic lipogenesis-associated genes. Copyright © 2017. Published by Elsevier B.V.

The role of hepatic mitochondria in the regulation of glucose metabolism in BHE rats

International Nuclear Information System (INIS)

Kim, M.J.C.

1988-01-01

The interacting effects of dietary fat source and thyroxine treatment on the hepatic mitochondrial function and glucose metabolism were studied. In the first study, three different sources of dietary fatty acids and thyroxine treatment were used to investigate the hepatic mitochondrial thermotropic behavior in two strains of rat. The NIDDM BHE and Sprague-Dawley rats were used. Feeding coconut oil increased serum T 4 levels and T 4 treatment increased serum T 3 levels in the BHE rats. In the mitochondria from BHE rats fed coconut oil and treated with T 4 , the transition temperature disappeared due to a decoupling of succinate supported respiration. This was not observed in the Sprague-Dawley rats. In the second study, two different sources of dietary fat and T 4 treatment were used to investigate hepatic mitochondrial function. Coconut oil feeding increased Ca ++ Mg ++ ATPase and Mg ++ ATPase. T 4 treatment had potentiated this effect. T 4 increased the malate-aspartate shuttle and α-glycerophosphate shuttle activities. In the third study, the glucose turnover rate from D-[ 14 C-U]/[6- 3 H]-glucose and gluconeogeneis from L-[ 14 C-U]-alanine was examined. Dietary fat or T 4 did not affect the glucose mass. T 4 increased the irreversible fractional glucose turnover rate

A relative study of hepatic perfusion and portal vein pressure in rats with liver cirrhosis

International Nuclear Information System (INIS)

Li Jiaping; Yang Jianyong; Chen Wei; Huang Yonghui

2006-01-01

Objective: To evaluate spiral CT perfusion in assessing portal vein pressure in rats with different stages of liver cirrhosis. Methods Seventeen rats with early stage of liver cirrhosis, 18 with intermediate stage, 12 with advanced stage, and 13 healthy rats as a control group were selected and recieved hepatic perfusion on a single-row spiral CT scanner. The parameters of hepatic perfusion were calculated using the deconvolution method. The portal vein pressure was measured by multi-physiographer. Results: (1) In study group, the PVP (portal venous perfusion) and THBP (total hepatic blood perfusion) were negatively correlated with FPP, while positively correlated with the HPI (hepatic perfusion index) and MTT (mean transit time). The FPP had a close relation with PVP. The equation, Y 20.671-3.195X, could be conducted with linear regression analysis. (2) According to the linear regression equation mentioned above, the FPP in 47 rats were 16.090±2.150 cmH 2 0, which was highly correlated with the observed valuel6.108±3.662 cmH 2 O (r=0.823 P<0.01). Conclusion: CT perfusion is a new non-invasive and efficient modality for assessment of the portal pressure in liver cirrhosis in various stages. (authors)

Sub-acute deltamethrin and fluoride toxicity induced hepatic oxidative stress and biochemical alterations in rats.

Science.gov (United States)

Dubey, Nitin; Khan, Adil Mehraj; Raina, Rajinder

2013-09-01

The current study investigated the effects of deltamethrin, fluoride (F(-)) and their combination on the hepatic oxidative stress and consequent alterations in blood biochemical markers of hepatic damage in rats. Significant hepatic oxidative stress and hepatic damage were observed in the toxicant exposed groups. These changes were higher in the deltamethrin-F(-) co-exposure treatment group, depicting a positive interaction between the two chemicals.

Age dependent in vitro metabolism of bifenthrin in rat and human hepatic microsomes.

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Nallani, Gopinath C; Chandrasekaran, Appavu; Kassahun, Kelem; Shen, Li; ElNaggar, Shaaban F; Liu, Zhiwei

2018-01-01

Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CL int ) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean V max (±SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (pbifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CL int values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes. Copyright © 2017 Elsevier Inc. All rights reserved.

FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

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Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

2016-01-01

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

Regulation of hepatic level of fatty-acid-binding protein by hormones and clofibric acid in the rat.

Science.gov (United States)

Nakagawa, S; Kawashima, Y; Hirose, A; Kozuka, H

1994-01-01

Regulation of the hepatic level of fatty-acid-binding protein (FABP) by hormones and p-chlorophenoxyisobutyric acid (clofibric acid) was studied. The hepatic level of FABP, measured as the oleic acid-binding capacity of the cytosolic FABP fraction, was decreased in streptozotocin-diabetic rats. The level of FABP was markedly increased in adrenalectomized rats, and the elevation was prevented by the administration of dexamethasone. Hypothyroidism decreased the level of FABP and hyperthyroidism increased it. A high correlation between the incorporation of [14C]oleic acid in vivo into hepatic triacylglycerol and the level of FABP was found for normal, diabetic and adrenalectomized rats. The level of FABP was increased by administration of clofibric acid to rats in any altered hormonal states, as was microsomal 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase, a peroxisome-proliferator-responsive parameter. These results suggest that the hepatic level of FABP is under regulation by multiple hormones and that clofibric acid induces FABP and 1-acyl-GPC acyltransferase by a mechanism which may be distinct from that by which hormones regulate the level of FABP. PMID:8110197

Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats.

Science.gov (United States)

Milton Prabu, S; Muthumani, M; Shagirtha, K

2012-04-01

The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats.

Intrahepatic upregulation of MRTF-A signaling contributes to increased hepatic vascular resistance in cirrhotic rats with portal hypertension.

Science.gov (United States)

Zheng, Lei; Qin, Jun; Sun, Longci; Gui, Liang; Zhang, Chihao; Huang, Yijun; Deng, Wensheng; Huang, An; Sun, Dong; Luo, Meng

2017-06-01

Portal hypertension in cirrhosis is mediated, in part, by increased intrahepatic resistance, reflecting massive structural changes associated with fibrosis and intrahepatic vasoconstriction. Activation of the Rho/MRTF/SRF signaling pathway is essential for the cellular regulatory network of fibrogenesis. The aim of this study was to investigate MRTF-A-mediated regulation of intrahepatic fibrogenesis in cirrhotic rats. Portal hypertension was induced in rats via an injection of CCl 4 oil. Hemodynamic measurements were obtained using a polyethylene PE-50 catheter and pressure transducers. Expression of hepatic fibrogenesis was measured using histological staining. Expression of protein was measured using western blotting. Upregulation of MRTF-A protein expression in the livers of rats with CCl 4 -induced cirrhosis was relevant to intrahepatic resistance and hepatic fibrogenesis in portal hypertensive rats with increased modeling time. Inhibition of MRTF-A by CCG-1423 decelerated hepatic fibrosis, decreased intrahepatic resistance and portal pressure, and alleviated portal hypertension. Increased intrahepatic resistance in rats with CCl 4 -induced portal hypertension is associated with an upregulation of MRTF-A signaling. Inhibition of this pathway in the liver can decrease hepatic fibrosis and intrahepatic resistance, as well as reduce portal pressure in cirrhotic rats with CCl 4 -induced portal hypertension. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Preventive effects of chronic exogenous growth hormone levels on diet-induced hepatic steatosis in rats

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Tian Ya-ping

2010-07-01

Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD, which is characterized by hepatic steatosis, can be reversed by early treatment. Several case reports have indicated that the administration of recombinant growth hormone (GH could improve fatty liver in GH-deficient patients. Here, we investigated whether chronic exogenous GH levels could improve hepatic steatosis induced by a high-fat diet in rats, and explored the underlying mechanisms. Results High-fat diet-fed rats developed abdominal obesity, fatty liver and insulin resistance. Chronic exogenous GH improved fatty liver, by reversing dyslipidaemia, fat accumulation and insulin resistance. Exogenous GH also reduced serum tumour necrosis factor-alpha (TNF-alpha levels, and ameliorated hepatic lipid peroxidation and oxidative stress. Hepatic fat deposition was also reduced by exogenous GH levels, as was the expression of adipocyte-derived adipokines (adiponectin, leptin and resistin, which might improve lipid metabolism and hepatic steatosis. Exogenous GH seems to improve fatty liver by reducing fat weight, improving insulin sensitivity and correcting oxidative stress, which may be achieved through phosphorylation or dephosphorylation of a group of signal transducers and activators of hepatic signal transduction pathways. Conclusions Chronic exogenous GH has positive effects on fatty liver and may be a potential clinical application in the prevention or reversal of fatty liver. However, chronic secretion of exogenous GH, even at a low level, may increase serum glucose and insulin levels in rats fed a standard diet, and thus increase the risk of insulin resistance.

Effects of 4-nonylphenol on oxidant/antioxidant balance system inducing hepatic steatosis in male rat

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Ansoumane Kourouma

2015-01-01

Full Text Available An emerging literature suggests that early life exposure to 4-nonylphenol (4-NP, a widespread endocrine disrupting chemical, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that intraperitoneal administration of 4-NP induces hepatic steatosis in rat. 24 male Sprague-Dawley rats were administered with 4-NP (0, 2, 10 and 50 mg/kg b.wt in corn oil for 30 days. Liver histology, biochemical analysis and gene expression profiling were examined. After treatment, abnormal liver morphology and function were observed in the 4-NP-treated rat, and significant changes in gene expression an indicator of hepatic steatosis and apoptosis were observed compared with controls. Up-regulated genes involved in apoptosis, hepatotoxity and oxidative stress, increased ROS and decrease of antioxidant enzyme were observed in the 4-NP exposed rat. Extensive fatty accumulation in liver section and elevated serum GOT, GPT, LDH and γ-GT were also observed. Incidence and severity of liver steatosis was scored and taken into consideration (steatosis, ballooning and lobular inflammation. Hepatocytes apoptosis could promote NAFLD progression; Fas/FasL, TNF-α and Caspase-9 mRNA activation were important contributing factors to hepatic steatosis. These findings provide the first evidence that 4-NP affects the gene expression related to liver hepatotoxicity, which is correlated with hepatic steatosis.

Dietary supplementation of blueberry juice enhances hepatic expression of metallothionein and attenuates liver fibrosis in rats.

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Yuping Wang

Full Text Available To investigate the effect of blueberry juice intake on rat liver fibrosis and its influence on hepatic antioxidant defense.Rabbiteye blueberry was used to prepare fresh juice to feed rats by daily gastric gavage. Dan-shao-hua-xian capsule (DSHX was used as a positive control for liver fibrosis protection. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injection of CCl4 and feeding a high-lipid/low-protein diet for 8 weeks. Hepatic fibrosis was evaluated by Masson staining. The expression of α-smooth muscle actin (α-SMA and collagen III (Col III were determined by immunohistochemical techniques. The activities of superoxide dismutase (SOD and malondialdehyde (MDA in liver homogenates were determined. Metallothionein (MT expression was detected by real-time RT-PCR and immunohistochemical techniques.Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT, increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver.Our study suggests that dietary supplementation of blueberry juice can augment antioxidative capability of the liver presumably via stimulating MT expression and SOD activity, which in turn promotes HSC inactivation and thus decreases extracellular matrix collagen accumulation in the liver, and thereby alleviating hepatic fibrosis.

Hepatic cysteamine and non-protein sulfhydryl levels following cystamine or cysteamine treatment of galactosamine-poisoned rats

International Nuclear Information System (INIS)

MacDonald, J.R.; Gandolfi, A.J.; Sipes, I.G.

1985-01-01

Hepatic cysteamine and non-protein sulfhydryl (NPSH) levels were determined in galactosamine (GAL)-poisoned rats following hepatoprotective cystamine or cysteamine treatments to determine whether alterations of hepatic NPSH status could contribute to their observed protective actions. D(+)-Galactosamine HC1 (400 mg/kg, ip) was administered to male Sprague-Dawley rats at 8 pm. Cystamine diHC1 (300 mg/kg, po) or cysteamine HC1 (170 mg/kg, ip) were administered 12 hr after GAL. Hepatic NPSH levels were determined using Ellman's reagent. Hepatic cysteamine levels were determined by separating NPSH Ellman's derivatives by reversed phase HPLC. Cystamine and cysteamine caused transient elevation of NPSH levels of 1-2 nanomoles/mg liver which correlated with the presence of 1-2 nanomoles of cysteamine/mg liver. However, neither cystamine nor cysteamine prevented NPSH levels from falling to 3 nanomoles/mg tissue 24 hr after GAL. Hepatoprotective treatments did not affect long term NPSH status in GAL-poisoned rats. However, transient NPSH increases, due to the intrahepatic presence of cysteamine, may contribute to the therapeutic effects of these hepatoprotective agents

Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats

NARCIS (Netherlands)

Vogels, B. A.; Maas, M. A.; Daalhuisen, J.; Quack, G.; Chamuleau, R. A.

1997-01-01

The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic

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.

Acute Ethanol Gavage Attenuates Hemorrhage/Resuscitation-Induced Hepatic Oxidative Stress in Rats

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B. Relja

2012-01-01

Full Text Available Acute ethanol intoxication increases the production of reactive oxygen species (ROS. Hemorrhagic shock with subsequent resuscitation (H/R also induces ROS resulting in cellular and hepatic damage in vivo. We examined the role of acute ethanol intoxication upon oxidative stress and subsequent hepatic cell death after H/R. 14 h before H/R, rats were gavaged with single dose of ethanol or saline (5 g/kg, EtOH and ctrl; H/R_EtOH or H/R_ctrl, resp.. Then, rats were hemorrhaged to a mean arterial blood pressure of 30±2 mmHg for 60 min and resuscitated. Two control groups underwent surgical procedures without H/R (sham_ctrl and sham_EtOH, resp.. Liver tissues were harvested at 2, 24, and 72 h after resuscitation. EtOH-gavage induced histological picture of acute fatty liver. Hepatic oxidative (4-hydroxynonenal, 4-HNE and nitrosative (3-nitrotyrosine, 3-NT stress were significantly reduced in EtOH-gavaged rats compared to controls after H/R. Proapoptotic caspase-8 and Bax expressions were markedly diminished in EtOH-gavaged animals compared with controls 2 h after resuscitation. EtOH-gavage increased antiapoptotic Bcl-2 gene expression compared with controls 2 h after resuscitation. iNOS protein expression increased following H/R but was attenuated in EtOH-gavaged animals after H/R. Taken together, the data suggest that acute EtOH-gavage may attenuate H/R-induced oxidative stress thereby reducing cellular injury in rat liver.

Modulatory role of kolaviron in phenytoin-induced hepatic and testicular dysfunctions in Wistar rats.

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Owoeye, Olatunde; Adedara, Isaac A; Adeyemo, Oluwatobi A; Bakare, Oluwafemi S; Egun, Christa; Farombi, Ebenezer O

2015-03-01

Phenytoin, an anticonvulsant agent used for the treatment of epilepsy has been reported to exhibit toxic side effects on the liver and testes. The present study investigated the protective effects of kolaviron (KV, a bioflavonoid from Garcinia kola seeds) against hepatic and testicular damage in rats exposed to phenytoin. The study consisted of four groups of six rats per group. Group I rats received 2 mL/kg of corn alone while group II received 75 mg/kg of phenytoin (PHT) alone. Groups III and IV were co-treated with kolaviron (200 mg/kg KV) and vitamin E (500 mg/kg VTE), respectively, for 14 days. The antioxidant status, hepatic and reproductive functional parameters were subsequently determined. PHT treatment significantly (p < 0.05) increased superoxide dismutase (SOD) and catalase (CAT) activities, elevated lipid peroxidation (LPO) and hydrogen peroxide (H2O2) levels along with significant reduction in the hepatic and testicular levels of glutathione (GSH). Moreover, PHT exposure elicited significant increases in alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels. The significant reduction in seminal epithelium thickness and the diameter of seminiferous tubules was accompanied with marked decrease in sperm motility, sperm count, and viability in PHT-treated rats. However, antioxidant status and the functional indices of liver and testes were restored to near control levels in rats co-treated with KV and VTE. In conclusion, KV and VTE protect the liver and testes against functional impairment due to PHT treatment.

Effects of Lactobacillus fermented soymilk and soy yogurt on hepatic lipid accumulation in rats fed a cholesterol-free diet.

Science.gov (United States)

Kitawaki, Ryoko; Nishimura, Yuko; Takagi, Naohiro; Iwasaki, Mitsuhiro; Tsuzuki, Kimiko; Fukuda, Mitsuru

2009-07-01

We examined the effects of lactic acid fermented soymilk, in which part of the soymilk was replaced with okara (soy yogurt), on plasma and hepatic lipid profiles in rats fed a cholesterol-free diet. Additionally, we investigated the effects of soy yogurt on hepatic gene expression in rats using DNA microarray analysis. Male Sprague-Dawley rats aged 5 weeks (n=5/group) were fed a control diet (AIN-93) or a test diet in which 20% of the diet was replaced by soy yogurt for 7 weeks. Soy yogurt consumption did not affect body weight or adipose tissue weight as compared with control diet. In the soy yogurt group, the liver weight and hepatic triglyceride content were significantly lower than the control group, and the level of plasma cholesterol was also lower. Furthermore, DNA microarray analysis indicated that soy yogurt ingestion down-regulated the expression of the SREBP-1 gene and enzymes related to lipogenesis in the rat liver, while expression of beta-oxidation-related genes was up-regulated. These results suggest that soy yogurt is beneficial in preventing hepatic lipid accumulation in rats.

Significance of glucagon for insulin secretion and hepatic glycogenolysis during exercise in rats

DEFF Research Database (Denmark)

Richter, Erik; Galbo, H; Holst, J J

1981-01-01

The significance of glucagon and of the sympatho-adrenal system for insulin secretion and hepatic glycogen depletion during exercise was studied. Male rats were either adrenodemedullated and chemically sympathectomized with 6-hydroxydopamine (SX) or sham-treated (C). During light ether anesthesia......, cardiac blood for glucose analysis and a biopsy of the liver were obtained, and either antigen-stripped glucagon antibodies (A) or control gamma globulins (N) in saline were injected through the cardiac cannula. Subsequently, the rats swam in tepid water (33-34 degree C) for 100 minutes with a tail weight...... attached (2% of body weight). Then cardiac blood was drawn for analysis of glucose, insulin and glucagon, and a sample of the liver was collected. In both CA and CN rats, the blood glucose concentration tended to increase (p less than 0.1) during exercise, whereas hepatic glycogen depletion and the plasma...

Comparative pharmacokinetics and tissue distribution profiles of lignan components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

Science.gov (United States)

Yang, Tao; Liu, Shan; Zheng, Tian-Hui; Tao, Yan-Yan; Liu, Cheng-Hai

2015-05-26

Fuzheng Huayu recipe (FZHY) is formulated on the basis of Chinese medicine theory in treating liver fibrosis. To illuminate the influence of the pathological state of liver fibrosis on the pharmacokinetics and tissue distribution profiles of lignan components from FZHY. Male Wistar rats were randomly divided into normal group and Hepatic fibrosis group (induced by dimethylnitrosamine). Six lignan components were detected and quantified by ultrahigh performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)in the plasma and tissue of normal and hepatic fibrosis rats. A rapid, sensitive and convenient UHPLC-MS/MS method has been developed for the simultaneous determination of six lignan components in different rat biological samples successfully. After oral administration of FZHY at a dose of 15g/kg, the pharmacokinetic behaviors of schizandrin A (SIA), schizandrin B (SIB), schizandrin C (SIC), schisandrol A (SOA), Schisandrol B (SOB) and schisantherin A (STA) have been significantly changed in hepatic fibrosis rats compared with the normal rats, and their AUC(0-t) values were increased by 235.09%, 388.44%, 223.30%, 669.30%, 295.08% and 267.63% orderly (Pdistribution results showed the amount of SIA, SIB, SOA and SOB were significant increased in heart, lung, spleen and kidney of hepatic fibrosis rats compared with normal rats at most of the time point (Pdistribution of lignan components in normal and hepatic fibrosis rats. The hepatic fibrosis could alter the pharmacokinetics and tissue distribution properties of lignan components in rats after administration of FZHY. The results might be helpful for guide the clinical application of this medicine. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dietary Supplementation of Blueberry Juice Enhances Hepatic Expression of Metallothionein and Attenuates Liver Fibrosis in Rats

Science.gov (United States)

Wang, Yuping; Cheng, Mingliang; Zhang, Baofang; Nie, Fei; Jiang, Hongmei

2013-01-01

Aim To investigate the effect of blueberry juice intake on rat liver fibrosis and its influence on hepatic antioxidant defense. Methods Rabbiteye blueberry was used to prepare fresh juice to feed rats by daily gastric gavage. Dan-shao-hua-xian capsule (DSHX) was used as a positive control for liver fibrosis protection. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injection of CCl4 and feeding a high-lipid/low-protein diet for 8 weeks. Hepatic fibrosis was evaluated by Masson staining. The expression of α-smooth muscle actin (α-SMA) and collagen III (Col III) were determined by immunohistochemical techniques. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenates were determined. Metallothionein (MT) expression was detected by real-time RT-PCR and immunohistochemical techniques. Results Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT), increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver. Conclusion Our study suggests that dietary supplementation of blueberry juice can augment antioxidative capability of the liver presumably via stimulating MT expression and SOD activity, which in turn promotes HSC inactivation and thus decreases extracellular matrix collagen accumulation in the liver, and thereby alleviating hepatic fibrosis. PMID:23554912

Effect of selected natural products, thioproline and pegasys on hepatic platelet activating factor (PAF) in CCL4-induced hepatic fibrosis in rats

International Nuclear Information System (INIS)

Badria, Farid A.

2007-01-01

This study aimed to estimate hepatic levels of platelet activating factor (PAF) in liver fibrosis induced by CCl4 in rats. A group of selected natural products; boswellic acids, curcumin and glycrrhizin (preparation named OMNI; a drug under clinical trials for treatment of hepatitis C virus), Mirazid (a commercially available schistomicidal drug), Thioproline (a commercially available hepatoprotective agent) and Pegasys (peg interferon alpha-2a; a commercially available therapy for treatment of Hepatitis C virus) were examined for their effect on hepatic PAF groups each comprised 9 rats. Group 1 was treated only with CCl4, group 2 to 5 were treated with OMNI, Mirazid, Thioproline and Pegasys, respectively whereas the 6th group was the normal control group (with no treatment, except an injection of the vehicle). Liver damage was induced in all groups except normal control group (groups 1 to 5) by i.p. injection of 40% CCl4 in corn oil (0.375 ml/kg) 3 times a week for 3 weeks. One week after CCl4 intoxication, all tested drugs were injected i.p. daily for 3 weeks. Hepatic PAF concentration was estimated by HPTLC (high performance thin layer chromatography), while levels of serum transminases (ALT, AST), hepatic hydroxyproline (as marker of liver fibrosis), serum malondialdehyde and catalase (as markers of oxidative stress) were estimated sepctrophotometrically. The hepatic PAF levels were significantly higher in CCl4 group (24.24+-2.01 pmol equiv. /mg) (p<0.001). Treatment with OMNI, Mirazid, Thioproline and Pegasys reduced hepatic PAF significantly to be 11.84+-0.22, 14.5+-1.00, 13.17+-0, 54 and 14.26+-1.09pmol equiv. /mg respectively. This study may add further rational to the anti-fibrotic activity of the tested drugs via reduction of hepatic PAF. (author)

Exposure to a northern contaminant mixture (NCM alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

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Ryan J Mailloux

Full Text Available Non-alcoholic fatty liver disease (NAFLD, defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with

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

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

Science.gov (United States)

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.

Pathological mechanisms of alcohol-induced hepatic portal hypertension in early stage fibrosis rat model.

Science.gov (United States)

Li, Jian; Niu, Jian-Zhao; Wang, Ji-Feng; Li, Yu; Tao, Xiao-Hua

2005-11-07

To study the role of hepatic sinusoidal capillarization and perisinusoidal fibrosis in rats with alcohol-induced portal hypertension and to discuss the pathological mechanisms of alcohol-induced hepatic portal hypertension. Fifty SD rats were divided into control group (n=20) and model group (n=30). Alcoholic liver fibrosis rat model was induced by intragastric infusion of a mixture containing alcohol, corn oil and pyrazole (1 000:250:3). Fifteen rats in each group were killed at wk 16. The diameter and pressure of portal vein were measured. Plasma hyaluronic acid (HA), type IV collagen (CoIV) and laminin (LN) were determined by radioimmunoassay. Liver tissue was fixed in formalin (10%) and 6-mum thick sections were routinely stained with Mallory and Sirius Red. Liver tissue was treated with rabbit polyclonal antibody against LN and ColIV. Hepatic non-parenchymal cells were isolated, total protein was extracted and separated by SDS-PAGE. MMP-2 and TIMP-1 protein expression was estimated by Western blotting. The diameter (2.207+/-0.096 vs 1.528+/-0.054 mm, Pportal vein were significantly higher in model group than those in the control group. Plasma HA (129.97+/-16.10 vs 73.09+/-2.38 ng/mL, Pmodel group. Abundant collagen deposited around the central vein of lobules, hepatic sinusoids and hepatocytes in model group. ColI and ColIII increased remarkably and perisinusoids were almost surrounded by ColIII. Immunohistochemical staining showed that ColIV protein level (0.130+/-0.007 vs 0.032+/-0.004, Pprotein level (0.152+/-0.005 vs 0.029+/-0.005, Pmodel group. MMP-2 protein expression (2.306+/-1.089 vs 0.612+/-0.081, Pprotein expression (3.015+/-1.364 vs 0.446+/-0.009, Pmodel group and TIMP-1 protein expression was evidently higher than MMP-2 protein expression (2.669+/-0.170 vs 1.695+/-0.008, Pportal hypertension in rats.

Fibrogenic response of hepatic stellate cells in ovariectomised rats exposed to ketogenic diet.

Science.gov (United States)

Bobowiec, R; Wojcik, M; Jaworska-Adamu, J; Tusinska, E

2013-02-01

The discrepancy about the role of estrogens in hepatic fibrogenesis and lack of studies addressed of ketogenic diet (KD) on hepatic stellate cells (HSC), prompted us to investigate the activity of HSC in control, KD- and thioacetamide (TAA)-administrated rats with different plasma concentration of estradiol (E2). HSC were isolated by the collagenase perfusion methods and separated by the Percoll gradient centrifugation. After the 4(th) and 8(th) day of incubation, lysates of HSC and the media were collected for further analysis. The HSC derived from KD-rats released remarkably more transforming growth factor (TGF)-β1 than cells obtained from animals fed with a standard diet. The ovariectomy of KD-rats markedly intensified the secretion of this fibrogenic cytokine on the 8(th) day of incubation (201.33 ±1 7.15 pg/ml). In HSC of rats exposed to E2, the TGF-β1 concentration did not exceed 157 ± 34.39 pg/ml. In respect to the collagen type I, the HSC obtained from ovariectomised KD-rats released an augmented amount of this ECM protein after the 8(th) day of culture (1.83 ± 0.14 U/ml). In the same time, higher quantities of ASMA appeared in the KD rats (1.41 ± 0.3 pg/mg protein). Exposition of rats to E2 did not markedly decrease the amount of ASMA. In summary, KD was able to induce morphological and functional changes in HSC, especially derived from rats deprived of ovarian estrogens. However, the preservation of E2 in ovariectomised rats didn't substantially alter the activation of HSC.

Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat

International Nuclear Information System (INIS)

Sorrell, M.F.; Nauss, J.M.; Donohue, T.M. Jr.; Tuma, D.J.

1983-01-01

The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate [ 14 C]glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring [ 14 C]leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, [ 14 C]fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration

Characterization of murine hepatitis virus (JHM) RNA from rats with experimental encephalomyelitis.

Science.gov (United States)

Jackson, D P; Percy, D H; Morris, V L

1984-09-01

When Wistar Furth rats are inoculated intracerebrally with the murine hepatitis virus JHM they often develop a demyelinating disease with resulting hind leg paralysis. Using an RNA transfer procedure and hybridization kinetic analysis, the virus-specific RNA in these rats was characterized. The pattern of JHM-specific RNA varied with individual infections of Wistar Furth rats. However, two species of JHM-specific RNA, the nucleocapsid and a 2.1-2.4 X 10(6)-Da RNA species were generally present. A general decrease in JHM-specific RNA in brains and spinal cord samples taken later than 20 days postinoculation was observed; however, JHM-specific RNA persisted in the spinal cord longer than in the brain of these rats.

Visceral organ mass and hepatic protein synthetic capacity in fed and fasted rats

International Nuclear Information System (INIS)

Burrin, D.G.; Britton, R.A.; Ferrell, C.L.

1986-01-01

Forty-two male rats (avg wt. = 320 g) were used to assess the effect of severe nutrient restriction (72 h fast) on visceral organ mass and hepatic protein synthetic capacity as measured by in vitro incorporation of U- 14 -C-VALINE ( 14 C-VAL) into isolated hepatocytes. Organ weights expressed as a percent of empty body weight for fed vs. fasted rats were; liver (5.21 +/- .54 vs 3.82 +/- .46), kidney (.87 +/- 0.6 vs .89 +/- .05), stomach (.60 +/- .06 vs .61 +/- .06), intestines (3.70 +/- .44 vs 3.41 +/- .37). No differences were observed in in vitro oxygen consumption (15.7 +/- 3.1 vs 16.1 +/- 3.3, umole min -1 g -1 dry tissue) or 14 -C VAL incorporation (4.93 +/- 1.28 vs 4.31 +/- 1.48, dpm min -1 mg -1 dry tissue) for hepatocytes from fed vs. fasted rats. Analysis of perfused liver tissue indicated fed rats had higher protein (152.1 +/- 16.3 vs 136.6 +/- 29.6, mg/g tissue) and RNA (8.81 +/- 1.66 vs 5.97 +/- 1.87, mg/g tissue) with lower DNA (2.19 +/- .31 vs 3.19 +/- .54, mg/g tissue) compared to fasted rats. Protein-nucleic acid ratios suggest liver tissue from fed rats had a greater capacity for protein synthesis compared to fasted rats, however, this was not evident from in vitro hepatocyte 14 -C VAL incorporation estimates. These data indicate that severe nutrient restriction (72 h fast) affects visceral organ mass largely by reduced liver and gut size as well as decreased hepatic protein synthetic capacity

Gastric emptying in rats with acetaminophen-induced hepatitis

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G. Hessel

1998-09-01

Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

Long-Time Choledochal Clamping in Wistar Rats Causes Biliary Obstruction Progressing to Hepatic Fibrosis.

Science.gov (United States)

Jorge, G D L; Tártaro, R R; Escanhoela, C A F; Boin, I D F S F

2016-09-01

Biliary complications are important causes of morbidity and mortality in patients undergoing hepatic surgery. The aim of the study was to evaluate late liver alterations after a long period of choledochal clamping in Wistar rats. Ten male Wistar rats, weighing 304 grams, anesthetized with sodium thiopental (25 mg/kg) and xylazine (10 mg/kg) intravenously, were distributed into 2 groups: the choledochal clamping group (CCG) and the operation sham group (OSG), with 5 animals each submitted to an abdominal incision. In the CCG, the choledochal was isolated, dissected, and clamped with a microvascular clamp for 40 minutes. After this occlusion time, the clamp was removed and the incision was closed. In the OSG the animals, under normal conditions, were submitted only to anesthesia and laparotomy for choledochal manipulation. In all animals, after the 31st day, a hepatic biopsy was carried out for histology and blood biochemical tests: total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase. The animals were euthanized under anesthesia. This research was approved by the Ethics Committee on Animal Use (CEUA, Unicamp, No. 2511-1). In the CCG, 100% of the animals showed bile duct dilatation, ductular proliferation, and portal inflammatory infiltrate; 60% showed regenerative nodule formation; and 80% had porta-porta septa and foci of necrosis, all of which were not found in the OSG. All CCG group biochemical tests had significant increases (P Wistar rats caused hepatic dysfunction and biochemical and histological injuries with degrees of distortion to the hepatic architecture. Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat

NARCIS (Netherlands)

Bosman, D. K.; van den Buijs, C. A.; de Haan, J. G.; Maas, M. A.; Chamuleau, R. A.

1991-01-01

Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic

Protective Effect of Ethyl Acetate Fraction of Stereospermum Suaveolens Against Hepatic Oxidative Stress in STZ Diabetic Rats.

Science.gov (United States)

Balasubramanian, Thirumalaiswamy; Senthilkumar, G P; Karthikeyan, M; Chatterjee, Tapan Kumar

2013-07-01

Stereospermum suaveolens is a folk remedy for the treatment of diabetes and liver disorders in southern parts of India. In the present study, the protective effect of the ethyl acetate fraction of ethanol extract from S. suaveolens against hepatic oxidative stress was evaluated in streptozotocin (STZ)-induced diabetic rats for 14 days. The ethyl acetate fraction was administered orally to the STZ diabetic rats at the doses of 200 and 400 mg/kg. Blood glucose level was measured according to glucose oxidase method. In order to determine hepatoprotective activity, changes in the levels of serum biomarker enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), and serum alkaline phosphatase (SALP) were assessed in the ethyl acetate fraction treated diabetic rats and were compared with the levels in diabetic control rats. In addition, the antioxidant activity of ethyl acetate fraction was evaluated using various hepatic parameters such as thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). It was found that administration of ethyl acetate fraction (200 and 400 mg/kg) produced a significant (P SALP, while elevating the GSH levels, and SOD and CAT activities in diabetic rats. Histopathologic studies also revealed the protective effect of ethyl acetate fraction on the liver tissues of diabetic rats. It was concluded from this study that the ethyl acetate fraction from ethanol extract of S. suaveolens modulates the activity of enzymatic and nonenzymatic antioxidants and enhances the defense against hepatic oxidative stress in STZ-induced diabetic rats.

Kombucha Tea Ameliorates Trichloroethylene Induced Hepatic Damages in Rats via Inhibition of Oxidative Stress and Free Radicals Induction

International Nuclear Information System (INIS)

Gharib, O.A.; Gharib, M.A.

2008-01-01

Kombucha Tea (KT) is reported to exhibit a wide variety of biological effects, including antioxidant. Evidence shows the important role of oxidative stress in the hepatic damage. The aim of this study is to investigate the possible protective effects of oral administration of KT in rats with trichloroethylene (TCE)-induced damage for ten consecutive days. Hepatic damage was evaluated by measuring total free radicals levels, biochemical and histological examinations. Serum gamma glutamyl transferase (GGT) activity (the hepatic damage marker), total protein, albumin and globulin as well as malonaldehyde (MDA), glutathione (GSH) content, nitric oxide (NO) concentration were evaluated in liver tissue homogenates. Total free radicals concentration in blood was examined by electron spin resonance (ESR). Total protein, DNA concentration, cell number and cell size in liver tissues were also examined. The rats orally administrated with TCE for ten days indicates hepatic damage changes, an increase in blood total free radicals concentration was observed, serum GGT activity, liver MDA, NO levels, total protein and decreased GSH content, DNA concentration and cell number. This accompanied with an increase in cell size of liver tissues, whereas KT reversed these effects. Furthermore, KT inhibits the concentration of total free radicals in blood and decreasing the increment of MDA and NO concentration. Histological studies reveal partial healing in those rats treated by KT after oral administration with TCE. The present results suggest that KT ameliorates TCE induced hepatic damage in rats probably due to its content of glucuronic, acetic acid and B vitamins via inhibition of oxidative stress and total free radicals

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

Science.gov (United States)

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.

Hepatic mitochondrial and microsomal recovery of rats intoxicated with CCl/sub 4/

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Hasegawa, T.; Hirai, Y.; Koga, N.; Tomokuni, K.

1983-01-01

The hepatic mitochondrial and microsomal recovery of rats intoxicated with CCl/sub 4/ was investigated with specific reference to the oxygen utilization of liver slices. In control rats, the major oxygen utilization of the liver slices was attributed to mitochondrial particles. Since the mitochondrial oxygen utilization was inhibited by cyanide, the microsomal oxygen utilization was induced by NADPH and phenobarbital (a substrate for microsomal mixed function oxidase). Changes in oxygen utilization were observed in the recovery course of rats intoxicated with CCl/sub 4/, and the recovery of mitochondria was found to be faster than that of microsomes. A sex difference was present in the recovery mechanism of the microsomes.

Chemoprotective effect of omega-3 fatty acids on thioacetamide induced hepatic fibrosis in male rats

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Atef M. Al-Attar

2017-05-01

Full Text Available The current study was designed to investigate the possible protective effect of omega-3 fatty acids from fish oil on hepatic fibrosis induced by thioacetamide (TAA in male rats. The experimental animals were divided into four groups. The first group was received saline solution and served as control. The second group was given 250 mg/kg body weight of TAA. The third group was treated with omega-3 fatty acids and TAA. The fourth group was given saline solution and supplemented with omega-3 fatty acids. Treatment of rats with TAA for three and six weeks resulted in a significant decrease in body weight gain, while the value of liver/body weight ratio was statistically increased. Furthermore, the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and total bilirubin were significantly increased. After three weeks of exposure to only TAA, liver sections showed an abnormal morphology characterized by noticeable fibrosis with the extracellular matrix collagen contents and damage of liver cells’ structure. Liver sections from rats treated with only TAA for six weeks revealed an obvious increase in extracellular matrix collagen content and bridging fibrosis. Treating TAA-intoxicated rats with omega-3 fatty acids significantly attenuated the severe physiological and histopathological changes. Finally, the present investigation suggests that omega-3 fatty acids could act against hepatic fibrosis induced by TAA due to its antioxidant properties, thus supporting its use in hepatic fibrosis therapy.

Ascorbic acid deficiency stimulates hepatic expression of inflammatory chemokine, cytokine-induced neutrophil chemoattractant-1, in scurvy-prone ODS rats.

Science.gov (United States)

Horio, Fumihiko; Kiyama, Keiichiro; Kobayashi, Misato; Kawai, Kaori; Tsuda, Takanori

2006-02-01

ODS rat has a hereditary defect in ascorbic acid biosynthesis and is a useful animal model for elucidating the physiological role of ascorbic acid. We previously demonstrated by using ODS rats that ascorbic acid deficiency changes the hepatic gene expression of acute phase proteins, as seen in acute inflammation. In this study, we investigated the effects of ascorbic acid deficiency on the production of inflammatory chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1), in ODS rats. Male ODS rats (6 wk of age) were fed a basal diet containing ascorbic acid (300 mg/kg diet) or a diet without ascorbic acid for 14 d. Obvious symptoms of scurvy were not observed in the ascorbic acid-deficient rats. Ascorbic acid deficiency significantly elevated the serum concentration of CINC-1 on d 14. The liver and spleen CINC-1 concentrations in the ascorbic acid-deficient rats were significantly elevated to 600% and 180% of the respective values in the control rats. However, the lung concentration of CINC-1 was not affected by ascorbic acid deficiency. Ascorbic acid deficiency significantly elevated the hepatic mRNA level of CINC-1 (to 480% of the value in the control rats), but not the lung mRNA level. These results demonstrate that ascorbic acid deficiency elevates the serum, liver and spleen concentrations of CINC-1 as seen in acute inflammation, and suggest that ascorbic acid deficiency stimulate the hepatic CINC-1 gene expression.

L-Carnitine Ameliorates Immunological-induced Hepatitis in rats

International Nuclear Information System (INIS)

Abd-Allah, Adel R.A.

2006-01-01

Immunological mediated hepatitis can be initiated by bacterial product; Lipopolysaccharide (LPS). The later is increased during severe infection, bacterial overgrowth or translocation. LPS stimulates Kupffer cells. Activation of the kupffer cells contributes to the onset of liver injuries by producing and releasing cytotoxic agents, inflammatory cytokines and reactive oxygen species. In the present study, L-carnitine, a natural antioxidant and immunoprotective agent, is used to protect against LPS-induced hepatitis. Liver content of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and the DNA adduct 8-hydroxydeoxyguanosine (8-HDG) are estimated. Serum activity of liver enzymes ALT, AST, and Gamma-GT, in addition to IL2 level are also estimated. Moreover, liver histopathological changes are determined. Results revealed that LPS (5mg/kg once i.p) significantly increased 8-HDG, MDA, NO and depleted GSH in the liver of the treated rats. It also increased serum IL2 and activity of all the estimated liver enzyme markers indicating massive hepatic cellular damage as also shown as a necrotic damage in liver histological sections. LCR administered (500mg/kg) 3h before LPS protected against LPS-induced lethality by 100%. LCR also prevented the increase in liver content of 8-HDG, MDA and NO. It reduced the depleted GSH and prevented the necrotic damage in the liver tissue as shown by normalization of ALT, AST and Gamma-Gt as well as IL2 and a remarkable improvement in liver histology. These data suggest that LCr could be used as an adjuvant therapy in severely infected and specific patients to counteract LPS-induced liver hepatitis. (author)

Effect of fumonisin B1 on rat hepatic P450 system

NARCIS (Netherlands)

Spotti, M.; Maas, R.F.M.; Nijs, C.M. de; Fink-Gremmels, J.

2000-01-01

The effects of the mycotoxin fumonisin B1 (FB1) on the hepatic cytochrome P450 system were investigated in male rats dosed daily by oral gavage with 3 mg FB1 per kg body weight for 9 consecutive days. FB1 treatment resulted in a reduced weight gain. At the same time, CYP2E activity was increased,

Soy compared with milk protein in a Western diet changes fecal microbiota and decreases hepatic steatosis in obese OLETF rats.

Science.gov (United States)

Panasevich, Matthew R; Schuster, Colin M; Phillips, Kathryn E; Meers, Grace M; Chintapalli, Sree V; Wankhade, Umesh D; Shankar, Kartik; Butteiger, Dustie N; Krul, Elaine S; Thyfault, John P; Rector, R Scott

2017-08-01

Soy protein is effective at preventing hepatic steatosis; however, the mechanisms are poorly understood. We tested the hypothesis that soy vs. dairy protein-based diet would alter microbiota and attenuate hepatic steatosis in hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Male OLETF rats were randomized to "Western" diets containing milk protein isolate (MPI), soy protein isolate (SPI) or 50:50 MPI/SPI (MS) (n=9-10/group; 21% kcal protein) for 16 weeks. SPI attenuated (Pcontent, and hepatic 16:1 n-7 and 18:1 n-7 PUFA concentrations) (Pbacterial 16S rRNA analysis revealed SPI-intake elicited increases (P<.05) in Lactobacillus and decreases (P<.05) in Blautia and Lachnospiraceae suggesting decreases in fecal secondary bile acids in SPI rats. SPI and MS exhibited greater (P<.05) hepatic Fxr, Fgfr4, Hnf4a, HmgCoA reductase and synthase mRNA expression compared with MPI. Overall, dietary SPI compared with MPI decreased hepatic steatosis and diacylglycerols, changed microbiota populations and altered bile acid signaling and cholesterol homeostasis in a rodent model of obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Green Tea Extract Encapsulated Into Chitosan Nanoparticles on Hepatic Fibrosis Collagen Fibers Assessed by Atomic Force Microscopy in Rat Hepatic Fibrosis Model.

Science.gov (United States)

Safer, Abdel-Majeed A; Hanafy, Nomany A; Bharali, Dhruba J; Cui, Huadong; Mousa, Shaker A

2015-09-01

The present study examined the effect of Green Tea Extract (GTE) encapsulated into Chitosan Nanoparticles (CS-NPs) on hepatic fibrosis in rat model as determined by atomic force microscopy (AFM). The bioactive compounds in GTE encapsulated into CS-NPs were determined using LC-MS/MS method. Additionally, the uptake of GTE-CS NPs in HepG2 cells showed enhanced uptake. In experimental fibrosis model, AFM was used as a high resolution microscopic tool to investigate collagen fibers as an indicator of hepatic fibrosis induced by treatment with CCl4. Paraffin sections of fibrotic liver tissues caused by CC4 treatment of rats and the effect of GTE-CS NPs treatment with or without CCl4 on hepatic fibrosis were examined. Liver tissues from the different groups of animals were de-waxed and processed as for normal H/E staining and Masson's trichrome staining to locate the proper area of ECM collagen in the CCl4 group versus collagen in liver tissues treated with the GTE-CS NPs with or without CCl4. Selected areas of paraffin sections were trimmed off and fixed flat on top of mica and inserted in the AFM stage. H/E staining, Masson's trichrome stained slides, and AFM images revealed that collagen fibers of 250 to 300 nm widths were abundant in the fibrotic liver samples while those of GTE-CS NPs were clear as in the control group. Data confirmed the hypothesis that GTE-CS NPs are effective in removing all the extracellular collagen caused by CCl4 in the hepatic fibrosis rat liver.

Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways.

Science.gov (United States)

El-Sherbeeny, Nagla A; Nader, Manar A; Attia, Ghalia M; Ateyya, Hayam

2016-12-01

Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

A Chinese Herbal Medicine, Jia-Wei-Xiao-Yao-San, Prevents Dimethylnitrosamine-Induced Hepatic Fibrosis in Rats

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Shu-Chen Chien

2014-01-01

Full Text Available Jia-wei-xiao-yao-san (JWXYS is a traditional Chinese herbal medicine that is widely used to treat neuropsychological disorders. Only a few of the hepatoprotective effects of JWXYS have been studied. The aim of this study was to investigate the hepatoprotective effects of JWXYS on dimethylnitrosamine- (DMN- induced chronic hepatitis and hepatic fibrosis in rats and to clarify the mechanism through which JWXYS exerts these effects. After the rats were treated with DMN for 3 weeks, serum glutamic oxaloacetic transaminase (SGOT and serum glutamic pyruvic transaminase (SGPT levels were significantly elevated, whereas the albumin level decreased. Although DMN was continually administered, after the 3 doses of JWXYS were orally administered, the SGOT and SGPT levels significantly decreased and the albumin level was significantly elevated. In addition, JWXYS treatment prevented liver fibrosis induced by DMN. JWXYS exhibited superoxide-dismutase-like activity and dose-dependently inhibited DMN-induced lipid peroxidation and xanthine oxidase activity in the liver of rats. Our findings suggest that JWXYS exerts antifibrotic effects against DMN-induced chronic hepatic injury. The possible mechanism is at least partially attributable to the ability of JWXYS to inhibit reactive-oxygen-species-induced membrane lipid peroxidation.

Protective Effect of Ethyl Acetate Fraction of Stereospermum Suaveolens Against Hepatic Oxidative Stress in STZ Diabetic Rats

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Thirumalaiswamy Balasubramanian

2013-07-01

Full Text Available Stereospermum suaveolens is a folk remedy for the treatment of diabetes and liver disorders in southern parts of India. In the present study, the protective effect of the ethyl acetate fraction of ethanol extract from S. suaveolens against hepatic oxidative stress was evaluated in streptozotocin (STZ-induced diabetic rats for 14 days. The ethyl acetate fraction was administered orally to the STZ diabetic rats at the doses of 200 and 400 mg/kg. Blood glucose level was measured according to glucose oxidase method. In order to determine hepatoprotective activity, changes in the levels of serum biomarker enzymes such as aspartate transaminase (AST, alanine transaminase (ALT, and serum alkaline phosphatase (SALP were assessed in the ethyl acetate fraction treated diabetic rats and were compared with the levels in diabetic control rats. In addition, the antioxidant activity of ethyl acetate fraction was evaluated using various hepatic parameters such as thiobarbituric acid reactive substances (TBARS, reduced glutathione (GSH, superoxide dismutase (SOD, and catalase (CAT. It was found that administration of ethyl acetate fraction (200 and 400 mg/kg produced a significant (P<0.001 fall in fasting blood glucose level, TBARS, bilirubin, AST, ALT, and SALP, while elevating the GSH levels, and SOD and CAT activities in diabetic rats. Histopathologic studies also revealed the protective effect of ethyl acetate fraction on the liver tissues of diabetic rats. It was concluded from this study that the ethyl acetate fraction from ethanol extract of S. suaveolens modulates the activity of enzymatic and nonenzymatic antioxidants and enhances the defense against hepatic oxidative stress in STZ-induced diabetic rats.

The antifibrotic effects of TGF-β1 siRNA on hepatic fibrosis in rats

International Nuclear Information System (INIS)

Lang, Qing; Liu, Qi; Xu, Ning; Qian, Ke-Li; Qi, Jing-Hu; Sun, Yin-Chun; Xiao, Lang; Shi, Xiao-Feng

2011-01-01

Highlights: → We constructed CCL4 induced liver fibrosis model successfully. → We proofed that the TGF-β1 siRNA had a definite therapy effect to CCL4 induced liver fibrosis. → The therapy effect of TGF-β1 siRNA had dose-dependent. -- Abstract: Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-β1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-β1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-β1 siRNA 0.125 mg/kg treatment group, TGF-β1 siRNA 0.25 mg/kg treatment group and TGF-β1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-β1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-β1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-β1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-β1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-β1 siRNA negative control group and the TGF-β1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the mRNA expression of TGF-β1, type I collagen and type III collagen (P < 0

The antifibrotic effects of TGF-{beta}1 siRNA on hepatic fibrosis in rats

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Lang, Qing; Liu, Qi [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China); Xu, Ning [The Second Hospital of YuLin, Shanxi Province (China); Qian, Ke-Li; Qi, Jing-Hu; Sun, Yin-Chun; Xiao, Lang [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China); Shi, Xiao-Feng, E-mail: sxff2003@yahoo.com.cn [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China)

2011-06-10

Highlights: {yields} We constructed CCL4 induced liver fibrosis model successfully. {yields} We proofed that the TGF-{beta}1 siRNA had a definite therapy effect to CCL4 induced liver fibrosis. {yields} The therapy effect of TGF-{beta}1 siRNA had dose-dependent. -- Abstract: Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-{beta}1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-{beta}1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-{beta}1 siRNA 0.125 mg/kg treatment group, TGF-{beta}1 siRNA 0.25 mg/kg treatment group and TGF-{beta}1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-{beta}1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-{beta}1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-{beta}1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-{beta}1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-{beta}1 siRNA negative control group and the TGF-{beta}1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the m

Investigation of hepatic fibrosis in rats with x-ray diffraction enhanced imaging

International Nuclear Information System (INIS)

Li Hui; Zhang Lu; Wang Xueyan; Luo Shuqian; Wang Tailing; Wang Baoen; Zhao Xinyan

2009-01-01

X-ray diffraction enhanced imaging (DEI) is a phase contrast technique that generates excellent contrast of biological soft tissues compared to conventional absorption radiography. We explore the application of DEI in the diagnosis of hepatic fibrosis. The produced refraction contrast images of fibrous rat liver samples show clearly abnormal liver architectures. Moreover, by comparing to histological pictures, different stages of fibrosis are discriminated, and the corresponding morphological features are analyzed. Besides, quantitative analyses of texture features are presented. The results reported herein show that DEI can be a potential noninvasive technique to diagnose and stage hepatic fibrosis

Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats

International Nuclear Information System (INIS)

Balaha, Mohamed; Kandeel, Samah; Barakat, Waleed

2016-01-01

Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1 ml/kg 10% CCL 4 in olive oil three times/week (every other day) for 12 weeks to induce hepatic cirrhosis. Carvedilol (10 mg/kg/day suspended in 0.5% CMC orally), silymarin (50 mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL 4 induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries. - Highlights: • Chronic liver damage ends into hepatocellular carcinoma in 5% of patients. • Persistent elevation of IL-6 induces hepatocarcinogenesis in chronic

Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats

Energy Technology Data Exchange (ETDEWEB)

Balaha, Mohamed, E-mail: Mohamed.Balaha@Med.Tanta.Edu.Eg [Pharmacology Department, Faculty of Medicine, Tanta University, El-Gish Street, Postal No. 31527 Tanta (Egypt); Kandeel, Samah [Histology Department, Faculty of Medicine, Tanta University, El-Gish Street, Postal No. 31527 Tanta (Egypt); Barakat, Waleed [Pharmacology Department, Faculty of Medicine, Tanta University, El-Gish Street, Postal No. 31527 Tanta (Egypt)

2016-11-15

Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1 ml/kg 10% CCL{sub 4} in olive oil three times/week (every other day) for 12 weeks to induce hepatic cirrhosis. Carvedilol (10 mg/kg/day suspended in 0.5% CMC orally), silymarin (50 mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL{sub 4} induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries. - Highlights: • Chronic liver damage ends into hepatocellular carcinoma in 5% of patients. • Persistent elevation of IL-6 induces hepatocarcinogenesis

Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats

International Nuclear Information System (INIS)

Konno, Yoshihiro; Sekimoto, Masashi; Nemoto, Kiyomitsu; Degawa, Masakuni

2004-01-01

Male and female of F344 rats were treated per os with nicardipine (Nic) and nifedipine (Nif), and changes in the levels of mRNA and protein of hepatic cytochrome P450 (P450) enzymes, CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP3A9, and CYP3A18 were examined. Furthermore, hepatic microsomal activities for pentoxyresorufin O-dealkylation (PROD) and nifedipine oxidation, which are mainly mediated by CYP2B and CYP3A subfamily enzymes, respectively, were measured. Analyses of RT-PCR and Western blotting revealed that Nic and Nif induced predominantly CYP3A and CYP2B enzymes, respectively. As for the gene activation of CYP2B enzymes, especially CYP2B1, Nif showed high capacity in both sexes of rats, whereas Nic did a definite capacity in the males but little in the females. Gene activations of CYP3A1, CYP3A2, and CYP3A18 by Nic occurred in both sexes of rats, although that of CYP3A9 did only in the male rats. Although gene activations of CYP3A1 and CYP3A2 by Nif were observed in both sexes of rats, a slight activation of the CYP3A9 gene occurred only in female rats, and the CYP3A18 gene activation, in neither male nor female rats. Thus, changes in levels of the mRNA or protein of CYP2B and CYP3A enzymes, especially CYP2B1 and CYP3A2, were closely correlated with those in hepatic PROD and nifedipine oxidation activities, respectively. The present findings demonstrate for the first time the sex difference in the Nic- and Nif-mediated induction of hepatic P450 enzymes in rats and further indicate that Nic and Nif show different specificities and sex dependencies in the induction of hepatic P450 enzymes

Black Seed Thymoquinone Improved Insulin Secretion, Hepatic Glycogen Storage, and Oxidative Stress in Streptozotocin-Induced Diabetic Male Wistar Rats

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Heba M. A. Abdelrazek

2018-01-01

Full Text Available Diabetes mellitus is one of the metabolic diseases having several complications. Nigella sativa oil (NSO might have beneficial effects in the treatment of diabetic complications. Thirty-two mature male Wistar rats were equally divided into four experimental groups: control, control NSO 2 mL/kg, streptozotocin- (STZ- induced diabetic, and diabetic (STZ-induced treated with oral NSO 2 mg/kg for 30 days. Fasting blood glucose (FBG, insulin, and lipid profile levels were determined. Pancreatic and hepatic tissues were used for catalase and GSH. Histopathology, hepatic glycogen contents, insulin immunohistochemistry, and pancreatic islet morphometry were performed. NSO 2 mL/kg was noticed to decrease (P<0.05 FBG and increase (P<0.05 insulin levels in diabetic rats than in diabetic nontreated animals. Lipid profile showed significant (P<0.5 improvement in diabetic rats that received NSO 2 mL/kg than in the diabetic group. Both pancreatic and hepatic catalase and GSH activities revealed a significant (P<0.05 increment in the diabetic group treated with NSO than in the diabetic animals. NSO improved the histopathological picture and hepatic glycogen contents of the diabetic group as well as increased (P<0.05 insulin immunoreactive parts % and mean pancreatic islet diameter. NSO exerts ameliorative and therapeutic effects on the STZ-induced diabetic male Wistar rats.

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

Science.gov (United States)

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.

Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia

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Li-Xia Shi

2017-01-01

Conclusions: These results indicate a decrease in expression of hepatic CYPs and their regulator GR in rats exposed to IH. Therefore, this should be noted for patients on medication, especially those on drugs metabolized via the hepatic system, and close attention should be paid to the liver function of patients with OSA-associated IH.

Nuclear ploidy of neonatal rat livers: effects of two hepatic carcinogens (mirex and dimethylnitrosamine)

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Carlson, J.; Abraham, R.

1985-01-01

The effect of two hepatic carcinogens, dimethylnitrosamine (DMN) (genotoxic) and mirex (epigenetic), on polyploidization in 12-d-old neonatal rats was investigated by Coulter counteranalysis and [ 3 H] thymidine uptake in isolated hepatic nuclear classes. DMN disturbed the normal ploidy development in the neonatal liver and the proportion of nuclei in the ploidy classes by inducing the premature formation of a significant population of tetraploids with a concommitant reduction in diploids. A great proportion of the replicative activity was present in tetraploid nuclei as measured by the incorporation of [ 3 H] thymidine. The labeling index and number of mitoses were also increased. In contrast to DMN, mirex had no influence on polyploidization. The neonatal rats used in these studies thus offer an opportunity to investigate in vivo the mode of action of genotoxic versus epigenetic compounds with reference to their effect on DNA

Effects of perfluorodecanoic(PFDA) and perfluorooctanoic (PFOA) acids on hepatic carnitine palmitoyltransferase (CPT) activity in rats

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Vanden Heuvel, J.P.; Kuslikis, B.I.; Peterson, R.E.

1990-01-01

PFDA has been hypothesized to cause a diversion of fatty acids from oxidation toward esterification in rat liver. Normal regulation of this partitioning is exerted by CPT, an enzyme inhibited by several peroxisome proliferators. Effects of the peroxisome proliferators PFDA and PFOA on hepatic mitochondrial fatty acid oxidation and CPT activity were examined. PFDA or PFOA added to isolated rat liver mitochondria in concentrations of 0.2, 2, 20 and 200 μg per mg mitochondrial protein had no effect on CPT activity nor on mitochondrial oxidation of [1- 14 C] palmitoyl-CoA or [1- 14 C] palmitoyl-carnitine (quantitated by 14 CO 2 plus acid soluble 14 C production). Three days after rats were treated with PFDA or PFOA (37.5 or 150 μmol/kg, ip) or vehicle, liver mitochondria were isolated. Mitochondrial oxidation of [1- 14 C] palmitoyl-CoA or [1- 14 C]palmitoyl-carnitine was unaffected by PFDA and PFOA. CPT activity and inhibition of CPT activity by malonyl-CoA was also unaffected by PFDA and PFOA. Therefore, PFDA and PFOA did not have a major inhibitory effect on hepatic mitochondrial oxidation of palmitoyl-CoA or palmitoyl-carnitine, nor did they interfere with hepatic CPT activity either in vitro or in vivo

Delayed plasma clearance and hepatic uptake of lymph chylomicron 14C-cholesterol in marginally zinc-deficient rats

International Nuclear Information System (INIS)

Koo, S.I.; Algilani, K.; Norvell, J.E.; Henderson, D.A.

1986-01-01

Previously, chylomicrons from marginally zinc-deficient rats were shown to be abnormally large, with markedly reduced levels of apoproteins C and E. In the present study, effects of such changes on the plasma clearance and hepatic uptake of chylomicron cholesterol were investigated in rats fed 3 ppm of zinc (ZD), as compared with those fed 30 ppm of zinc (CT). The rate of plasma clearance was determined by plasma 14C-radioactivity at different intervals after intravenous injection of lymph chylomicrons labeled in vivo with 14C-cholesterol. The 14C-clearance curves were nonlinear, consisting of an initial rapid phase followed by a slow phase of clearance. The initial 14C-clearance was significantly (p less than 0.05) delayed whether the labeled chylomicrons from ZD donors were injected into ZD or CT recipients. The hepatic 14C-recovery in extracted lipids was also significantly lower in ZD rats. The present data provide first evidence that a marginal level of zinc deficiency produces a significant delay in the plasma clearance and hepatic uptake of chylomicron cholesterol. This may be attributable in part to the molecular alterations of chylomicrons induced by zinc deficiency

Influence of chronic stress on the compositions of hepatic cholesterol and triglyceride in male Wistar rats fed a high fat diet.

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Gao, Siyuan; Han, Xue; Fu, Jihua; Yuan, Xiaoling; Sun, Xing; Li, Qiang

2012-07-01

  We determined the influence of chronic stress (CS) on the compositions of hepatic cholesterol and triglyceride (TG) in rats fed a high fat diet (HFD).   Male Wistar rats were fed either a standard diet or a HFD and half of the HFD fed rats were given CS (electric foot shock assisted with noise) for 8 weeks.   Compared with the control group, the levels of hepatic total cholesterol (TC) and TG were significantly elevated in the HFD and HFD with chronic stress (HFD+CS) groups, and the more severe elevations of them were found in the HFD group. Inversely, the more severe elevations of hepatic water-soluble parts of TC and TG were found in the HFD+CS group, as the elevations of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol in liver and serum, tumor necrosis factor-α, interleukin-1β and malondialdehyde in liver. Meanwhile, downregulated mRNA expressions of hepatic liver X receptor-α (LXR-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) were also more severe in the HFD+CS group.   CS can aggravate the high levels of water-soluble compositions of hepatic TC and TG induced by HFD as it aggravates hepatic inflammation and oxidative stress; in spite of that, however, it cannot further promote hepatic lipidosis. This is consistent with the downregulated mRNA expressions of LXR-α and PPAR-γ. © 2012 The Japan Society of Hepatology.

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

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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).

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.

Use of unripe plantain (Musa paradisiaca) in the management of diabetes and hepatic dysfunction in streptozotocin induced diabetes in rats.

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Eleazu, Chinedum O; Okafor, Polycarp

2015-03-01

This study aims to investigate the effect of unripe plantain (Musa paradisiaca) on markers of hepatic dysfunction in streptozotocin induced diabetic rats. Blood glucose; relative liver weight (RLW); relative kidney weight (RKW); relative heart weight (RHW); relative pancreatic weight (RPW); serum and hepatic serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP); serum amylase, lipase, total, and conjugated bilirubin; and chemical analysis of the test feed were determined using standard techniques. The diabetic rats had significant alteration (P 0.05) in the RHW of the rats in the three groups, as well as significant decreases (P 0.05) in the amylase levels of the rats fed unripe plantain compared with the nondiabetic rats. The test and standard rat feeds contained considerable amount of proteins, carbohydrates, fats, phenols, and crude fiber. Amelioration of acute pancreatitis by unripe plantain could play a key role in its management of diabetes and related complications.

3,5 Diiodo-L-Thyronine (T2 Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats.

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Daniel F Vatner

Full Text Available Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD, and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2 reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% ± 10 in T2-treated rats as compared with 47% ± 4 suppression in the vehicle group (p = 0.32. This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003. There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a, genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase, and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase. Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be

Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

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Ganji, Shobha H; Kukes, Gary D; Lambrecht, Nils; Kashyap, Moti L; Kamanna, Vaijinath S

2014-02-15

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

Clofibrate improves glucose tolerance in fat-fed rats but decreases hepatic glucose consumption capacity

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Gustafson, LA; Kuipers, F; Wiegman, C; Sauerwein, HP; Romijn, JA; Meijer, AJ

2002-01-01

Background/Aims: High-fat (HF) diets cause glucose intolerance. Fibrates improve glucose tolerance. We have tried to obtain information on possible hepatic mechanisms contributing to this effect. Methods: Rats were fed a HF diet, isocaloric with the control diet, for 3 weeks without or with

Soy compared with milk protein in a western diet changes fecal microbiota and decreases hepatic steatosis in obese OLETF rats

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Soy protein is effective at preventing hepatic steatosis; however, the mechanisms are poorly understood. We tested the hypothesis that soy versus dairy protein-based diet would alter microbiota and attenuate hepatic steatosis in hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF ...

Ionone Derivatives from the Mycelium of Phellinus linteus and the Inhibitory Effect on Activated Rat Hepatic Stellate Cells

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Shiow-Chyn Huang

2016-05-01

Full Text Available Three new γ-ionylideneacetic acid derivatives, phellinulins A–C (1–3, were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1 was subjected to the examination of effects on activated rat hepatic stellate cells and exhibited significant inhibition of hepatic fibrosis.

The effect of down-regulation of Smad3 by RNAi on hepatic stellate cells and a carbon tetrachloride-induced rat model of hepatic fibrosis

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Z.R. Wang

2011-02-01

Full Text Available Searching for effective Smad3 gene-based gene therapies for hepatic fibrosis, we constructed siRNA expression plasmids targeting the rat Smad3 gene and then delivered these plasmids into hepatic stellate cells (HSCs. The effect of siRNAs on the mRNA levels of Smad2, Smad3, Smad4, and collagens I-α1, III-α1 and IV-α1 (Colα1, Col3α1, Col4α1, respectively was determined by RT-PCR. Eighty adult male Sprague-Dawley rats were randomly divided into three groups. Twice a week for 8 weeks, the untreated hepatic fibrosis model (N = 30 and the treated group (N = 20 were injected subcutaneously with 40% (v/v carbon tetrachloride (CCl4-olive oil (3 mL/kg, and the normal control group (N = 30 was injected with olive oil (3 mL/kg. In the 4th week, the treated rats were injected subcutaneously with liposome-encapsulated plasmids (150 µg/kg into the right liver lobe under general anesthesia once every 2 weeks, and the untreated rats were injected with the same volume of buffer. At the end of the 6th and 8th weeks, liver tissue and sera were collected. Pathological changes were assessed by a semi-quantitative scoring system (SSS, and a radioimmunoassay was used to establish a serum liver fibrosis index (type III procollagen, type IV collagen, laminin, and hyaluronic acid. The mRNA expression levels of the above cited genes were reduced in the HSCs transfected with the siRNA expression plasmids. Moreover, in the treated group, fibrosis evaluated by the SSS was significantly reduced (P < 0.05 and the serum indices were greatly improved (P < 0.01. These results suggest that Smad3 siRNA expression plasmids have an anti-fibrotic effect.

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.

Effects of Arctium lappa aqueous extract on lipid profile and hepatic enzyme levels of sucrose-induced metabolic syndrome in female rats

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Akram Ahangarpour

Full Text Available ABSTRACT Arctium lappa is known to have antioxidant and antidiabetic effects in traditional medicine. Objectives: The aim of this paper was to study the effects of A. lappa root extract (AE on lipid profile and hepatic enzyme levels in sucrose-induced metabolic syndrome (MS in female rats. The study used 40 adult female Wistar rats weighing 150 g-250 g randomly divided into five groups: control, metabolic syndrome (MS, metabolic syndrome+AE at 50,100, 200 mg/kg. MS was induced by administering 50% sucrose in drinking water for 6 weeks. AE was intra-peritoneally administered daily at doses of 50,100, and 200 mg/kg for two sequential weeks at the end of the fourth week in metabolic syndrome rats. Twenty-four hours after the last administration of AE, blood was collected and centrifuged, and then the serum was used for the measurement of lipid profile and hepatic enzyme. Serum glucose, insulin, fasting insulin resistance index, body weight, water intake, lipid profile, and hepatic enzymes were significantly increased although food intake was decreased in MS rats compared to the control rats. The lipids and liver enzymes were reduced by AE extracts in the MS group. This study showed that the A. lappa root aqueous extract exhibits a hypolipidemic activity of hyperlipidemic rats. This activity is practically that of a triple-impact antioxidant, hypolipidemic, and hepatoprotective.

Increased binding of LDL and VLDL to apo B,E receptors of hepatic plasma membrane of rats treated with Fibernat.

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Venkatesan, Nandini; Devaraj, S Niranjali; Devaraj, H

2003-10-01

Research has focussed on the hypocholesterolemic effects of certain types of dietary fiber such as enhancing conversion of hepatic cholesterol to bile acids or increase in catabolism of low density lipoprotein (LDL) via the apo B,E receptor. The effect of oral administration of a unique fibre cocktail of fenugreek seed powder, guar gum and wheat bran (Fibernat) and its varied effects on some aspects of lipid metabolism and cholesterol homeostasis in rats were examined. Rats were administered Fibernat along with the atherogenic diet containing 1.5 % cholesterol and 0.1 % cholic acid. Amounts of hepatic lipids, hepatic and fecal bile acids and activity of hepatic triglyceride lipase (HTGL) were determined. Transmission electron microscopic examination of the liver tissue and extent of uptake of (125)I-LDL and (125)I-VLDL by the hepatic apo B,E receptor was carried out. Food intake and body weight gain were similar between the 3 different dietary groups. Fibernat intake significantly increased apo B,E receptor expression in rat liver as reflected by an increase in the maximum binding capacity (B(max)) of the apo B,E receptor to (125)I-LDL and (125)I-VLDL. The activity of HTGL was increased by approximately 1.5-fold in Fibernat-fed rats as compared to those fed the atherogenic diet alone. A marked hypocholesterolemic effect was observed. Cholesterol homeostasis was achieved in Fibernat-fed rats. Two possible mechanisms are postulated to be responsible for the observed hypocholesterolemic effect a) an increase in conversion of cholesterol to bile acids and b) possibly by intra-luminal binding which resulted in increased fecal excretion of bile acids and neutral sterols. The resulting reduction in cholesterol content of liver cells coupled with upregulation of hepatic apo B,E receptors and increased clearance of circulating atherogenic lipoproteins-LDL and very low density lipoprotein (LDL and VLDL)-is the main mechanism involved in the hypocholesterolemic effect of

Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague–Dawley rats and C57BL/6 mice

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Nault, Rance; Kim, Suntae; Zacharewski, Timothy R., E-mail: tzachare@msu.edu

2013-03-01

Although the structure and function of the AhR are conserved, emerging evidence suggests that downstream effects are species-specific. In this study, rat hepatic gene expression data from the DrugMatrix database (National Toxicology Program) were compared to mouse hepatic whole-genome gene expression data following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the DrugMatrix study, male Sprague–Dawley rats were gavaged daily with 20 μg/kg TCDD for 1, 3 and 5 days, while female C57BL/6 ovariectomized mice were examined 1, 3 and 7 days after a single oral gavage of 30 μg/kg TCDD. A total of 649 rat and 1386 mouse genes (|fold change| ≥ 1.5, P1(t) ≥ 0.99) were differentially expressed following treatment. HomoloGene identified 11,708 orthologs represented across the rat Affymetrix 230 2.0 GeneChip (12,310 total orthologs), and the mouse 4 × 44K v.1 Agilent oligonucleotide array (17,578 total orthologs). Comparative analysis found 563 and 922 orthologs differentially expressed in response to TCDD in the rat and mouse, respectively, with 70 responses associated with immune function and lipid metabolism in common to both. Moreover, QRTPCR analysis of Ceacam1, showed divergent expression (induced in rat; repressed in mouse) functionally consistent with TCDD-elicited hepatic steatosis in the mouse but not the rat. Functional analysis identified orthologs involved in nucleotide binding and acetyltransferase activity in rat, while mouse-specific responses were associated with steroid, phospholipid, fatty acid, and carbohydrate metabolism. These results provide further evidence that TCDD elicits species-specific regulation of distinct gene networks, and outlines considerations for future comparisons of publicly available microarray datasets. - Highlights: ► We performed a whole-genome comparison of TCDD-regulated genes in mice and rats. ► Previous species comparisons were extended using data from the DrugMatrix database. ► Less than 15% of TCDD

Solanum nigrum Protects against Hepatic Fibrosis via Suppression of Hyperglycemia in High-Fat/Ethanol Diet-Induced Rats

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Cheng-Jeng Tai

2016-02-01

Full Text Available Background: Advanced glycation end products (AGEs signal through the receptor for AGE (RAGE, which can lead to hepatic fibrosis in hyperglycemia and hyperlipidemia. We investigated the inhibitory effect of aqueous extracts from Solanum nigrum (AESN on AGEs-induced RAGE signaling and activation of hepatic stellate cells (HSCs and hyperglycemia induced by high-fat diet with ethanol. Methods: An animal model was used to evaluate the anti-hepatic fibrosis activity of AESN in rats fed a high-fat diet (HFD; 30% with ethanol (10%. Male Wistar rats (4 weeks of age were randomly divided into four groups (n = 6: (1 control (basal diet; (2 HFD (30% + ethanol (10% (HFD/ethanol; (3 HFD/ethanol + AESN (100 mg/kg, oral administration; and (4 HFD/ethanol + pioglitazone (10 mg/kg, oral administration and treated with HFD for 6 months in the presence or absence of 10% ethanol in dietary water. Results: We found that AESN improved insulin resistance and hyperinsulinemia, and downregulated lipogenesis via regulation of the peroxisome proliferator-activated receptor α (PPARα, PPARγ co-activator (PGC-1α, carbohydrate response element-binding protein (ChREBP, acetyl-CoA carboxylase (ACC, and fatty acid synthase (FAS mRNA levels in the liver of HFD/ethanol-treated rats. In turn, AESN may delay and inhibit the progression of hepatic fibrosis, including α-smooth muscle actin (α-SMA inhibition and MMP-2 production. Conclusions: These results suggest that AESN may be further explored as a novel anti-fibrotic strategy for the prevention of liver disease.

The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1

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Shu, Nan; Hu, Mengyue; Ling, Zhaoli; Liu, Peihua; Wang, Fan; Xu, Ping; Zhong, Zeyu; Sun, Binbin; Zhang, Mian; Li, Feng; Xie, Qiushi; Liu, Xiaodong; Liu, Li

2016-01-01

Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation. PMID:27624558

Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet

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Sugatani Junko

2012-03-01

Full Text Available Abstract Background Rats fed a high-fat and high-sucrose (HF diet develop hepatic steatosis and hyperlipidemia. There are several reports that a change in nutritional status affects hepatic levels of drug-metabolizing enzymes. Synthetic inulin is a dietary component that completely evades glucide digestion. Supplementing a HF diet with inulin ameliorates hypertriglycemia and hepatic steatosis, but not hypercholesterolemia. This study aimed at distinguishing the effects of synthetic inulin and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin, which inhibit cholesterol biosynthesis. Methods We examined effects of co-treatment with synthetic inulin (5% and fluvastatin (0, 4, and 8 mg/kg, per os on body weight, epidydimal white adipose tissue weight, serum and hepatic lipid profiles, and hepatic cytochrome P450 (CYP mRNA and protein profiles in rats fed a standard diet or a HF diet for 3 weeks. Results Treatment with the synthetic inulin (5% or fluvastatin at 4 mg/kg (lethal dose in rats fed the HF diet, 8 mg/kg ameliorated the elevation in hepatic triacylglycerol and total cholesterol levels in rats fed the HF diet. Whereas co-treatment with the inulin (5% and fluvastatin (4 mg/kg had a tendency to more strongly suppress the elevation in serum levels of very low density lipoprotein triacylglycerol than either treatment alone, no additive or synergistic effect was found in decrease in hepatic lipid levels. Hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein and methoxyresorufin O-demethylase and ethoxyresorufin O-deethylase activities were reduced in rats fed the HF diet. The synthetic inulin alleviated the reduction in hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein more strongly than fluvastatin, and no synergistic effects were observed on co-treatment. Furthermore, hepatic levels of aryl hydrocarbon receptor mRNA were decreased in rats fed the HF diet and recovered to near normal values with the intake of dietary inulin

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.

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

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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.

Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats.

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Chen, Yung-Tsung; Lin, Yu-Chun; Lin, Jin-Seng; Yang, Ning-Sun; Chen, Ming-Ju

2018-04-01

Non-alcoholic fatty liver disease (NAFLD) is a common disease that is concomitant with obesity, resulting in increased mortality. To date, the efficiency of NAFLD treatment still needs to be improved. Therefore, we aimed to evaluate the effect of Lactobacillus mali APS1, which was isolated from sugary kefir, on hepatic steatosis in rats fed a high-fat diet (HFD). Sprague Dawley rats were fed a control diet, a HFD with saline, and a HFD with APS1 intervention by gavage daily for 12 weeks. The results showed that APS1 significantly reduced body weight and body weight gain in HFD-fed rats. APS1 reduced hepatic lipid accumulation by regulating SIRT-1/PGC-1α/SREBP-1 expression. Moreover, APS1 increased hepatic antioxidant activity by modulating Nrf-2/HO-1 expression. Notably, APS1 manipulated the gut microbiota, resulting in increasing proportions of the phylum Bacteroidetes/Firmicutes and reducing the abundance of specific NAFLD-associated bacteria. These results suggested that APS1 ameliorated hepatic steatosis by modulating lipid metabolism and antioxidant activity via manipulating specific NAFLD-associated gut microbiota in vivo. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

188Re-SSS lipiodol: radiolabelling and biodistribution following injection into the hepatic artery of rats bearing hepatoma.

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Garin, Etienne; Denizot, Benoit; Noiret, Nicolas; Lepareur, Nicolas; Roux, Jerome; Moreau, Myriam; Herry, Jean-Yves; Bourguet, Patrick; Benoit, Jean-Pierre; Lejeune, Jean-Jacques

2004-10-01

Although intra-arterial radiation therapy with 131I-lipiodol is a useful therapeutic approach to the treatment of hepatocellular carcinoma, various disadvantages limit its use. To describe the development of a method for the labelling of lipiodol with 188Re-SSS (188Re (S2CPh)(S3CPh)2 complex) and to investigate its biodistribution after injection into the hepatic artery of rats with hepatoma. 188Re-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 188Re, in cold lipiodol. The radiochemical purity (RCP) of labelling was checked immediately. The 188Re-SSS lipiodol was injected into the hepatic artery of nine rats with a Novikoff hepatoma. They were sacrificed 1, 24 and 48 h after injection, and used for ex vivo counting. Labelling of 188Re-SSS lipiodol was achieved with a yield of 97.3+/-2.1%. The immediate RCP was 94.1+/-1.7%. Ex vivo counting confirmed a predominantly hepatic uptake, with a good tumoral retention of 188Re-SSS lipiodol, a weak pulmonary uptake and a very faint digestive uptake. The 'tumour/non-tumoral liver' ratio was high at 1, 24 and 48 h after injection (2.9+/-1.5, 4.1+/-/4.1 and 4.1+/-0.7, respectively). Using the method described here, 188Re-SSS lipiodol can be obtained with a very high yield and a satisfactory RCP. The biodistribution in rats with hepatoma indicates a good tumoral retention of 188Re-SSS lipiodol associated with a predominant hepatic uptake, a weak pulmonary uptake and a very faint digestive uptake. This product should be considered for intra-arterial radiation therapy in human hepatoma.

Subacute effects of hexabromocyclododecane (HBCD) on hepatic gene expression profiles in rats

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Canton, Rocio F.; Peijnenburg, Ad A.C.M.; Hoogenboom, Ron L.A.P.; Piersma, Aldert H.; Ven, Leo T.M. van der; Berg, Martin van den; Heneweer, Marjoke

2008-01-01

Hexabromoyclododecane (HBCD), used as flame retardant (FR) mainly in textile industry and in polystyrene foam manufacture, has been identified as a contaminant at levels comparable to other brominated FRs (BFRs). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. The toxicological database of HBCD is too limited to perform at present a solid risk assessment, combining data from exposure and effect studies. In order to fill in some gaps, a 28-day HBCD repeated dose study (OECD407) was done in Wistar rats. In the present work liver tissues from these animals were used for gene expression profile analysis. Results show clear gender specificity with females having a higher number of regulated genes and therefore being more sensitive to HBCD than males. Several specific pathways were found to be affected by HBCD exposure, like PPAR-mediated regulation of lipid metabolism, triacylglycerol metabolism, cholesterol biosynthesis, and phase I and II pathways. These results were corroborated with quantitative RT-PCR analysis. Cholesterol biosynthesis and lipid metabolism were especially down-regulated in females. Genes involved in phase I and II metabolism were up-regulated predominantly in males, which could explain the observed lower HBCD hepatic disposition in male rats in this 28-day study. These sex-specific differences in gene expression profiles could also underlie sex-specific differences in toxicity (e.g. decreased thyroid hormone or increased serum cholesterol levels). To our knowledge, this is the fist study that describes the changes in rat hepatic gene profiles caused by this commonly used flame retardant

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity.

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Kishida, Tomoyuki; Onozato, Tomoya; Kanazawa, Toru; Tanaka, Satoru; Kuroda, Junji

2012-01-01

Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is well known to induce idiosyncratic hepatotoxicity. Although there remains much to be elucidated about its onset mechanism, it is widely accepted as a hypothesis that idiosyncratic hepatotoxicity arises from a specific immune response to a hapten formed by covalent binding of drugs or their reactive metabolites to hepatic tissues. In this study, we investigated the effects of covalent binding of DCF reactive metabolites to hepatic tissues using a rat model of liver injury induced by co-treatment with lipopolysaccharide (LPS) at a non-hepatotoxic dose. In studies done in vitro using hepatic microsomes prepared from rats treated with LPS alone, 4'- and 5-hydroxylation activities on DCF metabolism and adducts of reactive metabolites to dansyl glutathione (dGSH) were markedly decreased associated with a decrease in total P450 content. However, in studies done in vivo, the LPS/DCF co-treatment significantly increased adducts of 5-hydroxydiclofenac (5-OH-DCF) to rat hepatic tissues and delayed the elimination of 5-OH-DCF from plasma. Furthermore, we investigated the effects of co-treatment on hepatic GSH level in rats. A decrease of hepatic GSH was observed with the LPS/DCF co-treatment but not with LPS or DCF alone. The results suggest that covalent binding of reactive metabolites via 5-OH-DCF to hepatic tissues may play an important role in the onset of DCF-induced idiosyncratic hepatotoxicity, especially under decreased GSH conditions.

Evaluation of Hepatic Steatosis by Using Acoustic Structure Quantification US in a Rat Model: Comparison with Pathologic Examination and MR Spectroscopy.

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Lee, Dong Ho; Lee, Jae Young; Lee, Kyung Bun; Han, Joon Koo

2017-11-01

Purpose To determine factors that significantly affect the focal disturbance (FD) ratio calculated with an acoustic structure quantification (ASQ) technique in a dietary-induced fatty liver disease rat model and to assess the diagnostic performance of the FD ratio in the assessment of hepatic steatosis by using histopathologic examination as a standard of reference. Materials and Methods Twenty-eight male F344 rats were fed a methionine-choline-deficient diet with a variable duration (3.5 days [half week] or 1, 2, 3, 4, 5, or 6 weeks; four rats in each group). A control group of four rats was maintained on a standard diet. At the end of each diet period, ASQ ultrasonography (US) and magnetic resonance (MR) spectroscopy were performed. Then, the rat was sacrificed and histopathologic examination of the liver was performed. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance of the FD ratio in the evaluation of the degree of hepatic steatosis. The Spearman correlation coefficient was calculated to assess the correlation between the ordinal values, and multivariate linear regression analysis was used to identify significant determinant factors for the FD ratio. Results The diagnostic performance of the FD ratio in the assessment of the degree of hepatic steatosis (area under the receiver operating characteristic curve: 1.000 for 5%-33% steatosis, 0.981 for >33% to 66% steatosis, and 0.965 for >66% steatosis) was excellent and was comparable to that of MR spectroscopy. There was a strong negative linear correlation between the FD ratio and the estimated fat fraction at MR spectroscopy (Spearman ρ, -0.903; P analysis showed that the degree of hepatic steatosis (P ratio. Conclusion The FD ratio may potentially provide good diagnostic performance in the assessment of the degree of hepatic steatosis, with a strong negative linear correlation with the estimated fat fraction at MR spectroscopy. The degree of steatosis and

Lead nitrate-induced development of hypercholesterolemia in rats: sterol-independent gene regulation of hepatic enzymes responsible for cholesterol homeostasis.

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Kojima, Misaki; Masui, Toshimitsu; Nemoto, Kiyomitsu; Degawa, Masakuni

2004-12-01

Changes in the gene expressions of hepatic enzymes responsible for cholesterol homeostasis were examined during the process of lead nitrate (LN)-induced development of hypercholesterolemia in male rats. Total cholesterol levels in the liver and serum were significantly increased at 3-72 h and 12-72 h, respectively, after LN-treatment (100 micromol/kg, i.v.). Despite the development of hypercholesterolemia, the genes for hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and other enzymes (FPPS, farnesyl diphosphate synthase; SQS, squalene synthase; CYP51, lanosterol 14alpha-demethylase) responsible for cholesterol biosynthesis were activated at 3-24 h and 12-18 h, respectively. On the other hand, the gene expression of cholesterol 7alpha-hydroxylase (CYP7A1), a catabolic enzyme of cholesterol, was remarkably suppressed at 3-72 h. The gene expression levels of cytokines interleukin-1beta (IL-1beta) and TNF-alpha, which activate the HMGR gene and suppress the CYP7A1 gene, were significantly increased at 1-3 h and 3-24 h, respectively. Furthermore, gene activation of SREBP-2, a gene activator of several cholesterogenic enzymes, occurred before the gene activations of FPPS, SQS and CYP51. This is the first report demonstrating sterol-independent gene regulation of hepatic enzymes responsible for cholesterol homeostasis in LN-treated male rats. The mechanisms for the altered-gene expressions of hepatic enzymes in LN-treated rats are discussed.

Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.

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Soo Jin Yang

Full Text Available BACKGROUND: Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ on hepatic steatosis. METHODS: To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg⁻¹·day⁻¹ by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes. RESULTS: RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α and Forkhead box O1 (Foxo1 in rat livers. AMP-activated protein kinase (AMPK phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035, suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects. CONCLUSION: Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress.

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Veličković, Nataša; Teofilović, Ana; Ilić, Dragana; Djordjevic, Ana; Vojnović Milutinović, Danijela; Petrović, Snježana; Preitner, Frederic; Tappy, Luc; Matić, Gordana

2018-05-29

High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1β, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser 307 . It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.

[EFFECT OF ACETYLCYSTEINE, CORVITIN AND THEIR COMBINATION ON THE FUNCTIONAL STATE OF LIVER IN RATS WITH PARACETAMOL INDUCED TOXIC HEPATITIS].

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Ghonghadze, M; Antelava, N; Liluashvili, K; Okujava, M; Pachkoria, K

2017-02-01

Nowadays drug-induced hepatotoxicity is urgent problem worldwide. Currently more than 1000 drugs are hepatotoxic and most often are the reason of acute fulminant hepatitis and hepatocellular failure, the states requiring liver transplantation. The paracetamol induced liver toxicity is related with accumulation of its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is the free radical and enhances peroxidation of lipids, disturbs the energy status and causes death of hepatocytes. During our research we investigated and assessed the efficacy of acetylcysteine, corvitin and their combination in rat model of paracetamol induced acute toxic hepatitis. The study was performed on mature white male Wistar rates with body mass 150-180 g. 50 rats were randomly divided into 5 groups (10 rats in each group). To get the model of acute toxic hepatitis single intraperitoneal injection of paracetamol solution was used (750 mg/kg). Toxic hepatitis was treated with intrapertoneal administration of 40mg/kg acetylcysteine or 100mg/kg corvitin, as well as with combination of these drugs. Monotherapy with acetylcysteine and corvitin of paracetamol induced toxic hepatitis improved the liver function, decreased relative mass of the liver and animal mortality. The treatment of toxic hepatitis was most effective in the case of simultaneous administration of acetylcysteine and corvitin. The normal value of laboratory tests (ALT, ACT, alkaline phosphatase, total and unconjugated bilirubin) was reached and mortality was not more observed. On the bases of obtained data was concluded that acetylcysteine and corvitin have almost equal hepatoprotective activity. The combination of two drugs actually improves the liver function. The most pronounced hepatoprotective effect may be due to synergic action of acetylcysteine and corvitin and such regime can be recommended for correction of liver function.

Dietary Supplementation with Virgin Coconut Oil Improves Lipid Profile and Hepatic Antioxidant Status and Has Potential Benefits on Cardiovascular Risk Indices in Normal Rats.

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Famurewa, Ademola C; Ekeleme-Egedigwe, Chima A; Nwali, Sophia C; Agbo, Ngozi N; Obi, Joy N; Ezechukwu, Goodness C

2018-05-04

Research findings that suggest beneficial health effects of dietary supplementation with virgin coconut oil (VCO) are limited in the published literature. This study investigated the in vivo effects of a 5-week VCO-supplemented diet on lipid profile, hepatic antioxidant status, hepatorenal function, and cardiovascular risk indices in normal rats. Rats were randomly divided into 3 groups: 1 control and 2 treatment groups (10% and 15% VCO-supplemented diets) for 5 weeks. Serum and homogenate samples were used to analyze lipid profile, hepatorenal function markers, hepatic activities of antioxidant enzymes, and malondialdehyde level. Lipid profile of animals fed VCO diets showed significant reduction in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels; high-density lipoprotein (HDL) level increased significantly (p risk indices. The level of malondialdehyde (MDA), a lipid peroxidation marker, remarkably reduced and activities of hepatic antioxidant enzymes-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)-were markedly increased in VCO diet-fed rats. The VCO diet significantly modulated creatinine, sodium (Na + ), potassium (K + ), chloride (Cl - ), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) compared to control. The findings suggest a beneficial effect of VCO on lipid profile, renal status, hepatic antioxidant defense system, and cardiovascular risk indices in rats.

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

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Li Y

2017-09-01

Full Text Available Yanmei Li,1,2 Ruibing Su,3 Shuqin Xu,2 Qingjun Huang,1 Haiyun Xu1,2 1The Mental Health Center, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 3Department of Forensics and Pathology, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China Abstract: Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects. Keywords: artesunate, clozapine, dyslipidemia, hepatic steatosis, schizophrenia 

Intraportal nicotine infusion in rats decreases hepatic blood flow through endothelin-1 and both endothelin A and endothelin B receptors

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Hashimoto, Takashi; Yoneda, Masashi; Shimada, Tadahito; Kurosawa, Mieko; Terano, Akira

2004-01-01

Smoking has been demonstrated to aggravate liver injury. Nicotine, a major pharmacological component of tobacco smoke, affects a multitude of functions. Smoking and nicotine induce synthesis of endothelin (ET)-1. The effect of intraportal infusion of nicotine on hepatic circulation and an involvement of ET-1 and ET receptor in the action of nicotine were investigated in rats. Nicotine (0-100 μg/kg/h) was infused into the portal vein of urethane-anesthetized rats, and changes of hepatic blood flow were evaluated. Intraportal infusion of nicotine dose-dependently decreased hepatic blood flow and increased portal pressure without any alteration of heart rate or arterial blood pressure. This action of intraportal nicotine was completely abolished by pretreatment of ET-1 antibody. Either BQ485 (ET A receptor antagonist) or BQ788 (ET B receptor antagonist) partially reversed the effect of nicotine, and combination of BQ788 and BQ485 completely abolished it. These findings suggest that nicotine inhibits hepatic circulation through ET-1, and ET A and ET B receptor

Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: Activation of PPAR-α

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Hsun-Wei Huang, Tom; Peng Gang; Qian Li, George; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

2006-01-01

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-α, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-α mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-α luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-α antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-α activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity

Enhanced hepatic insulin signaling in the livers of high altitude native rats under basal conditions and in the livers of low altitude native rats under insulin stimulation: a mechanistic study.

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Al Dera, Hussain; Eleawa, Samy M; Al-Hashem, Fahaid H; Mahzari, Moeber M; Hoja, Ibrahim; Al Khateeb, Mahmoud

2017-07-01

This study was designed to investigate the role of the liver in lowering fasting blood glucose levels (FBG) in rats native to high (HA) and low altitude (LA) areas. As compared with LA natives, besides the improved insulin and glucose tolerance, HA native rats had lower FBG, at least mediated by inhibition of hepatic gluconeogenesis and activation of glycogen synthesis. An effect that is mediated by the enhancement of hepatic insulin signaling mediated by the decreased phosphorylation of TSC induced inhibition of mTOR function. Such effect was independent of activation of AMPK nor stabilization of HIF1α, but most probably due to oxidative stress induced REDD1 expression. However, under insulin stimulation, and in spite of the less activated mTOR function in HA native rats, LA native rats had higher glycogen content and reduced levels of gluconeogenic enzymes with a more enhanced insulin signaling, mainly due to higher levels of p-IRS1 (tyr612).

Vitamin C and E chronic supplementation differentially affect hepatic insulin signaling in rats.

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Ali, Mennatallah A; Eid, Rania M H M; Hanafi, Mervat Y

2018-02-01

Vitamin C and vitamin E supplementations and their beneficial effects on type 2 diabetes mellitus (T2DM) have been subjected to countless controversial data. Hence, our aim is to investigate the hepatic molecular mechanisms of any diabetic predisposing risk of the chronic administration of different doses of vitamin E or vitamin C in rats. The rats were supplemented with different doses of vitamin C or vitamin E for eight months. Vitamin C and vitamin E increased fasting blood glucose, insulin, and homeostasis model assessment index for insulin resistance (HOMA). Vitamin C disrupted glucose tolerance by attenuating upstream hepatic insulin action through impairing the phosphorylation and activation of insulin receptor and its subsequent substrates; however, vitamin E showed its effect downstream insulin receptor in the insulin signaling pathway, reducing hepatic glucose transporter-2 (GLUT2) and phosphorylated protein kinase (p-Akt). Moreover, both vitamins showed their antioxidant capabilities [nuclear factor-erythroid-2-related factor 2 (Nrf2), total and reduced glutathione] and their negative effect on Wnt pathway [phosphorylated glycogen synthase kinase-3β (p-GSK-3β)], by altering the previously mentioned parameters, inevitably leading to severe reduction of reactive oxygen species (ROS) below the physiological levels. In conclusion, a detrimental effect of chronic antioxidant vitamins supplementation was detected; leading to insulin resistance and impaired glucose tolerance obviously through different mechanisms. Overall, these findings indicate that the conventional view that vitamins promote health benefits and delay chronic illnesses and aging should be modified or applied with caution. Copyright © 2017. Published by Elsevier Inc.

Bisphenol A induces oxidative stress and DNA damage in hepatic tissue of female rat offspring

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Jehane I. Eid

2015-08-01

Full Text Available Bisphenol A (BPA is an endocrine disrupting compound widely spread in our living environment. It is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to the limited information concerning the effect of BPA on the liver, the present study was designed to assess hepatic tissue injury induced by early life exposure to BPA in female rat offspring. Rat dams (n = 9 were gavaged with 0.5 and 50 mg of BPA/kg b.w./day throughout lactation until weaning. The sham group received olive oil for the same duration while the control group did not receive any injection. The liver tissue was collected from female pups at different pubertal periods (PND50, 90 and 110 to evaluate oxidative stress biomarkers, extent of DNA damage and histopathological changes. Our results indicated that early life exposure to BPA significantly increased oxidative/nitrosative stress, decreased antioxidant enzyme activities, induced DNA damage and chronic severe inflammation in the hepatic tissue in a time dependent manner. These data suggested that BPA causes long-term adverse effects on the liver, which leads to deleterious effects in the liver of female rat offspring.

Virgin coconut oil reverses hepatic steatosis by restoring redox homeostasis and lipid metabolism in male Wistar rats.

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Narayanankutty, Arunaksharan; Palliyil, Devika Mukundan; Kuruvilla, Kezia; Raghavamenon, Achuthan C

2018-03-01

Hepatosteatosis, a form of nonalcoholic fatty liver disease (NAFLD), is being increasingly recognized as a major health burden worldwide. Insulin resistance, dyslipidemia and imbalances in adipokine/cytokine interplay are reported to be involved in the onset and progression of this disease. Use of dietary nutraceuticals in prevention and treatment of NAFLD is emerging. Virgin coconut oil (VCO), a fermented product of fresh coconut kernel, has been shown to impede the development of hepatosteatosis in rats. This study analyzes the potential of VCO to reverse the already developed hepatosteatosis condition. Hyperglycemia, reduced glucose tolerance, dyslipidemia, and hepatic macrovesicles in high-fructose-diet-fed rats (4 weeks) confirmed the development of hepatosteatosis. Natural reversion in these parameters was observed upon shifting to normal diet in untreated control animals. Administration of VCO, however, increased this natural reversion by improving high-density lipoprotein cholesterol level (53.5%) and reducing hepatic and serum triacylglycerols (78.0 and 51.7%). Increased hepatic glutathione level (P < 0.01), antioxidant enzyme activities (P < 0.05) and reduced lipid peroxidation were also noticed in these animals. These observations were in concordance with reduced liver enzyme activities (P < 0.01) and restoration of altered hepatic architecture. The study indicates that VCO can be used as a nutraceutical against hepatosteatosis. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Daily fluctuation of hepatic P450 monooxygenase activities in male rats is controlled by the suprachiasmatic nucleus but remains unaffected by adrenal hormones.

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Furukawa, T; Manabe, S; Watanabe, T; Sehata, S; Sharyo, S; Okada, T; Mori, Y

1999-09-01

Hepatic P450 monooxygenase activities, which strongly influence the efficacy and/or toxicity of drugs, are known to fluctuate daily. We also know that the P450 activities assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities fluctuate daily, with apparently high values during the dark period in male rats. However, there is little knowledge about the factors that regulate daily fluctuation of P450 monooxygenase activities. In the present study using rats, we induced lesions in the suprachiasmatic nucleus (SCN) of the brain, the known site of the body's internal clock, and examined the effects on the daily fluctuation of the ACD activities to clarify the relationship between the SCN and the daily fluctuation of P450 monooxygenase activities. In addition, adrenalectomy was performed to re-evaluate the influence of adrenal hormones on the P450 activities. Our results indicated that daily fluctuations of the hepatic ACD activities were completely eliminated in the SCN-lesioned rats. However, the ACD activities in the adrenalectomized rats showed apparent daily fluctuations with high values during the dark period and low values during the light period. Therefore, this study demonstrated that the daily fluctuation of the hepatic P450 monooxygenase activities in male rats is controlled by the SCN but remains unaffected by the adrenal hormones.

Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV-infected SD rats through AMPK activation

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Zhan WL

2017-10-01

Full Text Available Weili Zhan, Yanhong Kang, Ning Chen, Chongshan Mao, Yi Kang, Jia Shang Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China Abstract: The hepatitis B virus (HBV has caused acute and chronic liver diseases in ~350 million infected people worldwide. Halofuginone (HF is a plant alkaloid which has been demonstrated to play a crucial role in immune regulation. Our present study explored the function of HF in the immune response of HBV-infected Sprague Dawley (SD rats. Plasmid containing pCDNA3.1-HBV1.3 was injected in SD rats for the construction of an acute HBV-infected animal model. Our data showed that HF reduced the high concentrations of serum hepatitis B e-antigen, hepatitis B surface antigen, and HBV DNA induced by HBV infection. HF also reduced the number of T helper (Th17 cells and the expression of interleukin (IL-17 compared with the pCDNA3.1-HBV1.3 group. Moreover, pro-inflammatory cytokine levels (IL-17, IL-23, interferon-γ, and IL-2 were downregulated and anti-inflammatory cytokine levels (IL-4 and IL-13 were upregulated by HF. Through further research we found that the expression of AMP-activated protein kinase (AMPK and IKBA which suppressed NF-κB activation was increased while the expression of p-NF-κB P65 was decreased in pCDNA3.1-HBV1.3+HF group compared with pCDNA3.1-HBV1.3 group, indicating that HF may work through the activation of AMPK. Finally, our conjecture was further verified by using the AMPK inhibitor compound C, which counteracted the anti-inflammation effect of HF, resulting in the decreased expression of AMPK, IKBA and increased expression of p-NF-κB P65 and reduced number of Th17 cells. In our present study, HF was considered as an anti-inflammatory factor in acute HBV-infected SD rats and worked through AMPK-mediated NF-κB p65 inactivation. This study implicated HF as a potential therapeutic strategy for hepatitis B. Keywords: halofuginone, hepatitis B virus

Expression of classical mediators in hearts of rats with hepatic dysfunction.

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Jarkovska, Dagmar; Bludovska, Monika; Mistrova, Eliska; Krizkova, Vera; Kotyzova, Dana; Kubikova, Tereza; Slavikova, Jana; Erek, Sumeyye Nur; Djordjevic, Aleksandar; Chottova Dvorakova, Magdalena

2017-11-01

Liver cirrhosis is associated with impairment of cardiovascular function including alterations of the heart innervation, humoral and nervous dysregulation, changes in systemic circulation and electrophysiological abnormalities. Choline acetyltransferase (ChAT), enzyme forming acetylcholine, tyrosine hydroxylase (TH), and dopamine-β-hydroxylase (DBH), enzymes participating in noradrenaline synthesis, are responsible for the production of classical neurotransmitters, and atrial natriuretic peptide (ANP) is produced by cardiomyocytes. The aim of this study was to evaluate the influence of experimentally induced hepatic dysfunction on the expression of proANP, ChAT, TH, and DBH in the heart. Hepatic dysfunction was induced by application of thioacetamide (TAA) or by ligation of bile duct. Biochemical parameters of hepatic injury and levels of peroxidation in the liver and heart were measured. Liver enzymes measured in the plasma were significantly elevated. Cardiac level of peroxidation was increased in operated but not TAA group animals. In the left atrium of operated rats, the expression of TH and DBH was lower, while expression of ChAT remained unchanged. In TAA group, no significant differences in the expression of the genes compared to controls were observed. Liver injury induced by ligation leads to an imbalance in the intracardiac innervation, which might impair nervous control of the heart.

Protective effect of thymoquinone against lead-induced hepatic toxicity in rats.

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Mabrouk, Aymen; Bel Hadj Salah, Imen; Chaieb, Wafa; Ben Cheikh, Hassen

2016-06-01

Lead (Pb) intoxication is a worldwide health problem which frequently affects the liver. This study was carried out to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver damage. Adult male rats were randomized into four groups: Control group received no treatment, Pb group was exposed to 2000 ppm Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per orally), and TQ group receiving only TQ. All treatments were applied for 5 weeks. Results indicated that Pb exposure increased hepatic Pb content, damaged hepatic histological structure (necrotic foci, hepatic strands disorganization, hypertrophied hepatocytes, cytoplasmic vacuolization, cytoplasmic loss, chromatin condensation, mononuclear cell infiltration, congestion, centrilobular swelling), and changed liver function investigated by plasma biochemical parameters (AST, ALT, ALP, γ-GT, LDH). Pb treatment also decreased total antioxidant status level and increased lipid peroxidation in the liver. Supplementation with TQ remarkably improved the Pb-induced adverse effects without significantly reducing the metal accumulation in the liver. In conclusion, our results indicate, for the first time, a protective effect of TQ against Pb-induced hepatotoxicity and suggest that this component might be clinically useful in Pb intoxication.

Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats.

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Junnila, M; Barak, A J; Beckenhauer, H C; Rahko, T

1998-10-01

Carbon tetrachloride-injected rats were given liquid diets with and without betaine for 7 d. Hepatic lipidosis was induced by 4 daily injections of carbon tetrachloride (CCl4). Animals were killed and their livers and blood taken for analysis of betaine, S-adenosylmethionine (SAM), betaine homocysteine methyltransferase (BHMT), triglyceride, alanine aminotransferase and aspartate aminotransferase. Liver samples were also processed and stained for histological examination. Supplemental betaine reduced triglyceride in the liver and centrilobular hepatic lipidosis induced by the CCl4 injections. In both the control and experimental groups receiving betaine, liver betaine, BHMT and SAM were significantly higher than in their respective groups not receiving betaine. This study provides evidence that betaine protects the liver against CCl4-induced lipidosis and may be a useful therapeutic and prophylactic agent in ameliorating the harmful effects of CCl4.

Experimental study of CT perfusion in hepatitis, hepatic fibrosis and early stage of cirrhosis

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Guan Sheng; Zhao Weidong; Zhou Kangrong; Peng Weijun; Mao Jian; Tang Feng; Wang Yong; Cao Guang; Sun Fei

2005-01-01

Objective: To investigate the value of CT perfusion in the early diagnosis of hepatic diffuse disease. Methods: Fourteen male Wistar rats of control group and 14 of test group at stages of hepatitis, hepatic fibrosis, hepatic cirrhosis which were induced with diethylnitrosamine (DEN), were studied with CT perfusion respectively. CT perfusion data of different stages were compared and pathologic analysis were performed. Results: Density-time curves of CT perfusion were satisfactory and all perfusion data could be obtained. During the period of hepatitis developing into early stage of hepatic cirrhosis, hepatic artery flow (HAF) trended to increase in test group, mean transmit time (MTT) prolonged obviously, blood flow (BF) and volume (BV) declined. While in control group, HAF declined slightly, MTT, BV and BF increased. Statistic analysis showed the differences of HAF and MTT at different stages between control and test groups were significant (P<0.05 ); the differences of BV and BF between hepatitis and hepatic cirrhosis, hepatic fibrosis and early stage of hepatic cirrhosis in test group were significant (P<0.05), but no significant difference between hepatitis and hepatic fibrosis. The corresponding pathologic changes at stage of hepatitis was swelling of hepatic cells; sinusoids cap illarization and deposition of collagen in the extravascular Disse's spaces were the main changes relating to hepatic blood perfusion at stage of fibrosis and early stage of cirrhosis. Conclusion: The method of CT scan can reflect some changes of hepatic blood perfusion in rats with hepatitis, hepatic fibrosis and early stage of cirrhosis. The data of CT perfusion, especially the changes should be valuable for clinical early diagnosis, treatment and follow-up. (authors)

Beneficial Effects of Phyllanthus amarus Against High Fructose Diet Induced Insulin Resistance and Hepatic Oxidative Stress in Male Wistar Rats.

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Putakala, Mallaiah; Gujjala, Sudhakara; Nukala, Srinivasulu; Desireddy, Saralakumari

2017-11-01

Insulin resistance (IR) is a characteristic feature of obesity, type 2 diabetes mellitus, and cardiovascular diseases. Emerging evidence suggests that the high-fructose consumption is a potential and important factor responsible for the rising incidence of IR. The present study investigates the beneficial effects of aqueous extract of Phyllanthus amarus (PAAE) on IR and oxidative stress in high-fructose (HF) fed male Wistar rats. HF diet (66% of fructose) and PAAE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 60 days. Fructose-fed rats showed weight gain, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin sensitivity, dyslipidemia, hyperleptinemia, and hypoadiponectinemia (P diet significantly ameliorated all these alterations. Regarding hepatic antioxidant status, higher lipid peroxidation and protein oxidation, lower reduced glutathione levels and lower activities of enzymatic antioxidants, and the histopathological changes like mild to severe distortion of the normal architecture as well as the prominence and widening of the liver sinusoids observed in the HF diet-fed rats were significantly prevented by PAAE treatment. These findings indicate that PAAE is beneficial in improving insulin sensitivity and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.

Açai (Euterpe oleracea Mart. Upregulates Paraoxonase 1 Gene Expression and Activity with Concomitant Reduction of Hepatic Steatosis in High-Fat Diet-Fed Rats

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Renata Rebeca Pereira

2016-01-01

Full Text Available Açai (Euterpe oleracea Mart., a fruit from the Amazon region, has emerged as a promising source of polyphenols. Açai consumption has been increasing owing to ascribed health benefits and antioxidant properties; however, its effects on hepatic injury are limited. In this study, we evaluated the antioxidant effect of filtered açai pulp on the expression of paraoxonase (PON isoforms and PON1 activity in rats with nonalcoholic fatty liver disease (NAFLD. The rats were fed a standard AIN-93M (control diet or a high-fat (HF diet containing 25% soy oil and 1% cholesterol with or without açai pulp (2 g/day for 6 weeks. Our results show that açai pulp prevented low-density lipoprotein (LDL oxidation, increased serum and hepatic PON1 activity, and upregulated the expression of PON1 and ApoA-I in the liver. In HF diet-fed rats, treatment with açai pulp attenuated liver damage, reducing fat infiltration and triglyceride (TG content. In rats receiving açai, increased serum PON1 activity was correlated with a reduction in hepatic steatosis and hepatic injury. These findings suggest the use of açai as a potential therapy for liver injuries, supporting the idea that dietary antioxidants are a promising approach to enhance the defensive systems against oxidative stress.

HEPATOPROTECTIVE ACTION OF THYMALINUM AND SUSPENSION OF RED BONE MARROW IN TREATING EXPERIMENTAL TOXIC HEPATITIS OF RATS

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E. F. Kulbekov

2014-01-01

Full Text Available Hepatic decompensation problems make it timely to search for the methods of its treatment. Stem cells usage in attempt to restore structures of organs and tissues is a promising direction of researches. However the problem of possible blast-cell transformation slows down studies in this direction. Attempt of thymalinum use as an antitumoral immune system's modulator may be successful and may widen the possibilities of stem cells use in hepatology. On the basis of toxical affection of rats' lever by tetrachloromethane and paracetamol we have studied hepatoprotective activity of thymalinum and suspension of rats' red bone marrow (RBM and a thymalinum + suspension of RBM complex. Hepatoprotective action was estimated by the volume of discharged bile of control group rats which received paracetamol comparing with intact animals. This confirms the absence of reliable hepatotoxical action of paracetamol following the methodology applied. Significant reduction of discharged bile volume of control group rats which received tetrachloromethane comparing with intact animals confirms the successfulness of the formation method of hepatitis model in animals which received tetrachloromethane. The animals which were given tetrachloromethane and thymalinum + suspension of RBM combination had bigger volume of bile discharged than control group animals. Hepatoprotective action tendency of thymalinum + suspension of RBM combination shown before on mice is also true for rats. 

Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

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Sarah M. DeNucci

2010-01-01

Full Text Available The finding of more severe steatohepatitis in alcohol fed Long Evans (LE compared with Sprague Dawley (SD and Fisher 344 (FS rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.

Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline

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Petry, T.W.; Bowden, G.T.; Huxtable, R.J.; Sipes, I.G.

1984-04-01

Hepatic DNA damage induced by the pyrrolizidine alkaloid monocrotaline was evaluated following i.p. administration to adult male Sprague-Dawley rats. Animals were treated with various doses ranging upward from 5 mg/kg, and hepatic nuclei were isolated 4 hr later. Hepatic nuclei were used as the DNA source in all experiments. DNA damage was characterized by the alkaline elution technique. A mixture of DNA-DNA interstrand cross-links and DNA-protein cross-links was induced. Following an injection of monocrotaline, 30 mg/kg i.p., DNA-DNA interstrand cross-linking reached a maximum within 12 hr or less and thereafter decreased over a protracted period of time. By 96 hr postadministration, the calculated cross-linking factor was no longer statistically different from zero. No evidence for the induction of DNA single-strand breaks was observed, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. These DNA cross-links may be related to the hepatocarcinogenic, hepatotoxic, and/or antimitotic effects of monocrotaline.

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

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

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Harrill, Joshua A. [The Hamner Institute for Health Sciences, Institute for Chemical Safety Sciences, RTP, NC 27709 (United States); Hukkanen, Renee R.; Lawson, Marie; Martin, Greg [The Dow Chemical Company, Midland, MI 48640 (United States); Gilger, Brian [North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606 (United States); Soldatow, Valerie [University of North Carolina, Department of Environmental Sciences and Engineering, Chapel Hill, NC 27599 (United States); LeCluyse, Edward L. [The Hamner Institute for Health Sciences, Institute for Chemical Safety Sciences, RTP, NC 27709 (United States); Budinsky, Robert A.; Rowlands, J. Craig [The Dow Chemical Company, Midland, MI 48640 (United States); Thomas, Russell S., E-mail: RThomas@thehamner.org [The Hamner Institute for Health Sciences, Institute for Chemical Safety Sciences, RTP, NC 27709 (United States)

2013-10-15

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague–Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expression of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ∼ 30–45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species. - Highlights: • An AHR knockout rat was generated on a Sprague–Dawley outbred background. • AHR-KO rats lack expression of AHR protein. • AHR-KO rats are insensitive to TCDD-mediated effects. • Data suggests difference in the role of AHR in tissue development of rats and mice. • Abnormalities in vascular

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

International Nuclear Information System (INIS)

Harrill, Joshua A.; Hukkanen, Renee R.; Lawson, Marie; Martin, Greg; Gilger, Brian; Soldatow, Valerie; LeCluyse, Edward L.; Budinsky, Robert A.; Rowlands, J. Craig; Thomas, Russell S.

2013-01-01

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague–Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expression of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ∼ 30–45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species. - Highlights: • An AHR knockout rat was generated on a Sprague–Dawley outbred background. • AHR-KO rats lack expression of AHR protein. • AHR-KO rats are insensitive to TCDD-mediated effects. • Data suggests difference in the role of AHR in tissue development of rats and mice. • Abnormalities in vascular

Pathophysiological appraisal of a rat model of total hepatic ischemia with an extracorporeal portosystemic shunt.

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Suzuki, S; Nakamura, S; Sakaguchi, T; Mitsuoka, H; Tsuchiya, Y; Kojima, Y; Konno, H; Baba, S

1998-11-01

Animal models of total hepatic ischemia (THI) and reperfusion injury are restricted by concomitant splanchnic congestion. This study was performed to determine the requirement suitable for an extracorporeal portosystemic shunt (PSS) to maintain the intestinal integrity in a rat model of THI. Using a polyethylene tube (0.86 or 1 mm i.d.), PSS was placed between the mesenteric and jugular veins. Comparison was done between THI models with or without PSS and a partial ischemia model with hepatectomy of the nonischemic lobes. Well-tolerated hepatic ischemic period, portal pressure after 10 min of hepatic ischemia, portal endotoxin levels at 1 h after reperfusion, histological features of the small bowel just before reperfusion, and local jejunal and ileal blood hemoglobin oxygen saturation index (ISO2) were compared among the models. Animals without PSS poorly tolerated 30 min of THI. Animals receiving THI with PSS or partial hepatic ischemia tolerated a longer ischemic period (60 min) with a significantly higher small bowel ISO2, lower portal pressure and endotoxin levels (P tube as well as partial hepatic ischemia were significantly lower than those after THI with PSS using a 0.86-mm i.d. tube. THI with PSS using a 1-mm i.d. tube was strikingly similar to partial hepatic ischemia in the pathophysiological profile during hepatic ischemia. PSS with a tube 1 mm or more in inner diameter offers pathophysiological advantages in experiments on THI and reperfusion. Copyright 1998 Academic Press.

Differential effects of low-fat and high-fat diets on fed-state hepatic triacylglycerol secretion, hepatic fatty acid profiles, and DGAT-1 protein expression in obese-prone Sprague–Dawley rats

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Heden, Timothy D.; Morris, E. Matthew; Kearney, Monica L.; Liu, Tzu-Wen; Park, Young-min; Kanaley, Jill A.; Thyfault, John P.

2015-01-01

The purpose of this study was to compare the effects of short-term low-fat (LF) and high-fat (HF) diets on fed-state hepatic triacylglycerol (TAG) secretion, the content of proteins involved in TAG assembly and secretion, fatty acid oxidation (FAO), and the fatty acid profile of stored TAG. Using selectively bred obese-prone Sprague–Dawley rats, we directly measured fed-state hepatic TAG secretion, using Tyloxapol (a lipoprotein lipase inhibitor) and a standardized oral mixed meal (45% carbohydrate, 40% fat, 15% protein) bolus in animals fed a HF or LF diet for 2 weeks, after which the rats were maintained on their respective diet for 1 week (washout) prior to the liver being excised to measure protein content, FAO, and TAG fatty acid profiles. Hepatic DGAT-1 protein expression was ~27% lower in HF- than in LF-fed animals (p < 0.05); the protein expression of all other molecules was similar in the 2 diets. The fed-state hepatic TAG secretion rate was ~39% lower (p < 0.05) in HF- (4.62 ± 0.18 mmol·h−1) than in LF- (7.60 ± 0.57 mmol·h−1) fed animals. Hepatic TAG content was ~2-fold higher (p < 0.05) in HF- (1.07 ± 0.15 nmol·g−1 tissue) than in LF- (0.50 ± 0.16 nmol·g−1 tissue) fed animals. In addition, the fatty acid profile of liver TAG in HF-fed animals closely resembled the diet, whereas in LF-fed animals, the fatty acid profile consisted of mostly de novo synthesized fatty acids. FAO was not altered by diet. LF and HF diets differentially alter fed-state hepatic TAG secretion, hepatic fatty acid profiles, and DGAT-1 protein expression. PMID:24669989

Differential effects of low-fat and high-fat diets on fed-state hepatic triacylglycerol secretion, hepatic fatty acid profiles, and DGAT-1 protein expression in obese-prone Sprague-Dawley rats.

Science.gov (United States)

Heden, Timothy D; Morris, E Matthew; Kearney, Monica L; Liu, Tzu-Wen; Park, Young-Min; Kanaley, Jill A; Thyfault, John P

2014-04-01

The purpose of this study was to compare the effects of short-term low-fat (LF) and high-fat (HF) diets on fed-state hepatic triacylglycerol (TAG) secretion, the content of proteins involved in TAG assembly and secretion, fatty acid oxidation (FAO), and the fatty acid profile of stored TAG. Using selectively bred obese-prone Sprague-Dawley rats, we directly measured fed-state hepatic TAG secretion, using Tyloxapol (a lipoprotein lipase inhibitor) and a standardized oral mixed meal (45% carbohydrate, 40% fat, 15% protein) bolus in animals fed a HF or LF diet for 2 weeks, after which the rats were maintained on their respective diet for 1 week (washout) prior to the liver being excised to measure protein content, FAO, and TAG fatty acid profiles. Hepatic DGAT-1 protein expression was ∼27% lower in HF- than in LF-fed animals (p < 0.05); the protein expression of all other molecules was similar in the 2 diets. The fed-state hepatic TAG secretion rate was ∼39% lower (p < 0.05) in HF- (4.62 ± 0.18 mmol·h(-1)) than in LF- (7.60 ± 0.57 mmol·h(-1)) fed animals. Hepatic TAG content was ∼2-fold higher (p < 0.05) in HF- (1.07 ± 0.15 nmol·g(-1) tissue) than in LF- (0.50 ± 0.16 nmol·g(-1) tissue) fed animals. In addition, the fatty acid profile of liver TAG in HF-fed animals closely resembled the diet, whereas in LF-fed animals, the fatty acid profile consisted of mostly de novo synthesized fatty acids. FAO was not altered by diet. LF and HF diets differentially alter fed-state hepatic TAG secretion, hepatic fatty acid profiles, and DGAT-1 protein expression.

Hepatic microsomal phospholipids in rats exposed intratracheally to coal fly ash

International Nuclear Information System (INIS)

Srivastava, P.K.; Chauhan, S.S.; Misra, U.K.

1986-01-01

The effects of intratracheal administration of fly ash (50 mg/kg body weight, daily for 7 days) on hepatic microsomal phospholipid metabolism has been studied in rats using various phospholipid precursors, viz NaH 2 32 PO 4 , (methyl- 14 C)-choline, and (methyl- 14 C)-methionine. Fly ash administration significantly increased microsomal phosphatidylcholine (PC), and lysophosphatidylcholine (LPC). The incorporation of NaH 2 32 PO 4 into total liver phospholipids, PC and Phosphatidyl ethanolamine (PE) was significantly increased in fly ash-treated rats as compared to the control. Fly ash administration also increased the incorporation of (methyl- 14 C)-choline into microsomal PC. Incorporation of (methyl- 14 C)-methionine into microsomal PC was not affected. Fly ash administration decreased the per cent distribution of arachidonic acid in PC and PE and increased that of oleic acid in PC and of linoleic acid in PE. (orig.)

Covalent interactions of 1,2,3-trichloropropane with hepatic macromolecules: studies in the male F-344 rat.

Science.gov (United States)

Weber, G L; Sipes, I G

1990-07-01

Preliminary investigations into the role of biotransformation in 1,2,3-trichloropropane (TCP)-induced tumor formation have been undertaken. Male F-344 rats were administered 30 mg/kg [14C]TCP (100 microCi/kg) ip and killed 4 hr later. The extent of covalent binding to hepatic protein, DNA, and RNA was 418, 244, and 432 pmol [14C]TCP equivalents/mg, respectively. An in vivo covalent binding time course showed no significant change in [14C]TCP equivalents bound to hepatic DNA (1-48 hr), while binding to protein was maximal by 4 hr and decreased significantly by 48 hr. The binding of TCP-associated radioactivity to hepatic protein and DNA was shown to be cumulative for two and three doses when given 24 hr apart. Pretreatment of animals with phenobarbital caused a decrease while pretreatment with SKF 525-A caused an increase in covalent binding of [14C]TCP equivalents to protein and DNA. Pretreatment of rats with beta-naphthoflavone did not alter the covalent binding of [14C]TCP equivalents to protein or DNA. However, glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. Intraperitoneal administration of TCP also depleted hepatic GSH by 41 and 61% 2 hr after doses of 30 and 100 mg/kg. The in vivo binding data suggest a dual role for GSH in the bioactivation of TCP. It may, in part, be that GSH is involved in the bioactivation and covalent binding of TCP to hepatic DNA. However, it also appears to detoxify a reactive intermediate(s) that binds to protein.

Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone.

Science.gov (United States)

Farley, Sherry M; Leonard, Scott W; Labut, Edwin M; Raines, Hannah F; Card, David J; Harrington, Dominic J; Mustacich, Debbie J; Traber, Maret G

2012-06-01

The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic α-tocopherol (α-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, α-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 μmol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either α-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, α-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C- or 7C-aglycone vitamin K metabolites, however, the urinary α-T metabolite (α-CEHC) increased ≥ 100-fold. Moreover, α-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. Thus, in rats, high tissue α-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of an alcoholic hepatic steatosis model induced by ethanol and high-fat diet in rats

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Carlos Eduardo Alves de Souza

2015-06-01

Full Text Available Alcoholic liver disease is characterized by a wide spectrum of liver damage, which increases when ethanol is associated with high-fat diets (HFD. This work aimed to establish a model of alcoholic hepatic steatosis (AHS by using a combination of 10% ethanol and sunflower seeds as the source of HFD. Male rats received water or 10% ethanol and regular chow diet and/or HFD, which consisted of sunflower seeds. The food consumption, liquid intake and body weight of the rats were monitored for 30 days. After this period, blood was collected for biochemical evaluation, and liver samples were collected for histological, mitochondrial enzyme activity and oxidative stress analyses. Our results indicated that the combination of 10% ethanol and HFD induced micro- and macrosteatosis and hepatocyte tumefaction, decreased the levels of reduced glutathione and glutathione S-transferase activity and increased the level of lipoperoxidation and superoxide dismutase activity. The mitochondrial oxidation of NADH and succinate were partially inhibited. Complexes I and II were the main inhibition sites. Hepatic steatosis was successfully induced after 4 weeks of the diet, and the liver function was modified. The combination of 10% ethanol and sunflower seeds as an HFD produced an inexpensive model to study AHS in rats.

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.

Metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes

Energy Technology Data Exchange (ETDEWEB)

Ohhira, Shuji; Watanabe, Masatomo; Matsui, Hisao [Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, 321-0293, Tochigi (Japan)

2003-03-01

Tributyltin and triphenyltin are metabolized by cytochrome P-450 system enzymes, and their metabolic fate may contribute to the toxicity of the chemicals. In the current study, the in vitro metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes was investigated to elucidate the metabolic competence for these compounds in humans. The metabolic reaction using microsome-NADPH system that is usually conducted was not applicable to in vitro metabolism of organotins, especially triphenyltin. We therefore examined the effects of dithiothreitol (DTT), one of the antioxidants for sulfhydryl groups, to determine the in vitro metabolism of tributyltin and triphenyltin. As a result, the treatment with 0.1 mM DTT in vitro increased the activity of the microsomal monooxygenase system for metabolism of tributyltin as well as triphenyltin; the total yield of tributyltin and triphenyltin metabolites as tin increased, respectively, by approximately 1.8 and 8.9 times for rat, 2.1 and 1.2 times for hamster, and 1.6 and 1.5 times for human. It is suggested that the organotins directly inactivate cytochrome P-450 because of the interaction with critical sulfhydryl groups of the hemoprotein. We confirmed the utility of this in vitro metabolic system using DTT in the hepatic microsomes of phenobarbital (PB)-pretreated and untreated hamsters. Thus, the in vitro metabolic system described here was applied to a comparative study of the metabolism of organotins in rats, hamsters and humans. Tributyltin was metabolized more readily than triphenyltin in all the species. In humans, the in vitro metabolic pattern resembled that of hamsters, which were susceptible to in vivo triphenyltin toxicity because of incompetent metabolism. It is possible that the hamster is a qualitatively and quantitatively suitable animal model for exploring the influence of tributyltin and triphenyltin in humans. (orig.)

Pre-existing liver cirrhosis reduced the toxic effect of diethylene glycol in a rat model due to the impaired hepatic alcohol dehydrogenase.

Science.gov (United States)

Ming Xing Huang; Xiao Mou Peng; Lin Gu; Gui Hua Chen

2011-09-01

Hepatic metabolizing enzymes of diethylene glycol (DEG) are impaired in liver diseases. Thus, the purpose of this study was to increase our understandings in metabolism and toxicology of DEG by clarifying the influences of pre-existing liver disease. Forty Sprague-Dawley rats with carbon tetrachloride-induced liver cirrhosis and 20 control rats were intraperitoneally administered a single dose of DEG, and randomly killed 1, 2, 5 or 8 days following exposure. Compared with control rats, the model rats had significantly higher blood CO(2)-combining power, lower blood urine nitrogen, serum creatinine and alanine aminotransferase levels on the second day and a lower mortality rate on the eighth day following DEG exposure. Enlargements of liver and kidneys and degeneration and necrosis of hepatocytes and renal tubules in the model rats was also less serious than in the control rats. Urine DEG levels were significantly higher on the first day in the model rats than the control rats (46.65 ± 8.79 mg vs 18.88 ± 6.18 mg, p activity in the model rats was significantly lower than that in the control rats, which was positively related to renal damage. The toxic effects of DEG in rats with pre-existing liver cirrhosis are significantly reduced, which may be due to the decreased hepatic ADH activity. It suggests that the metabolite of ADH is responsible for DEG poisoning, and this toxic metabolite may mainly originate in the liver.

Cocoa butter and safflower oil elicit different effects on hepatic gene expression and lipid metabolism in rats.

Science.gov (United States)

Gustavsson, Carolina; Parini, Paolo; Ostojic, Jovanca; Cheung, Louisa; Hu, Jin; Zadjali, Fahad; Tahir, Faheem; Brismar, Kerstin; Norstedt, Gunnar; Tollet-Egnell, Petra

2009-11-01

The aim of this study was to compare the effects of cocoa butter and safflower oil on hepatic transcript profiles, lipid metabolism and insulin sensitivity in healthy rats. Cocoa butter-based high-fat feeding for 3 days did not affect plasma total triglyceride (TG) levels or TG-rich VLDL particles or hepatic insulin sensitivity, but changes in hepatic gene expression were induced that might lead to increased lipid synthesis, lipotoxicity, inflammation and insulin resistance if maintained. Safflower oil increased hepatic beta-oxidation, was beneficial in terms of circulating TG-rich VLDL particles, but led to reduced hepatic insulin sensitivity. The effects of safflower oil on hepatic gene expression were partly overlapping with those exerted by cocoa butter, but fewer transcripts from anabolic pathways were altered. Increased hepatic cholesterol levels and increased expression of hepatic CYP7A1 and ABCG5 mRNA, important gene products in bile acid production and cholesterol excretion, were specific effects elicited by safflower oil only. Common effects on gene expression included increased levels of p8, DIG-1 IGFBP-1 and FGF21, and reduced levels of SCD-1 and SCD-2. This indicates that a lipid-induced program for hepatic lipid disposal and cell survival was induced by 3 days of high-fat feeding, independent on the lipid source. Based on the results, we speculate that hepatic TG infiltration leads to reduced expression of SCD-1, which might mediate either neutral, beneficial or unfavorable effects on hepatic metabolism upon high-fat feeding, depending on which fatty acids were provided by the diet.

Short-chain chlorinated paraffins (SCCPs) induced thyroid disruption by enhancement of hepatic thyroid hormone influx and degradation in male Sprague Dawley rats.

Science.gov (United States)

Gong, Yufeng; Zhang, Haijun; Geng, Ningbo; Xing, Liguo; Fan, Jingfeng; Luo, Yun; Song, Xiaoyao; Ren, Xiaoqian; Wang, Feidi; Chen, Jiping

2018-06-01

Short-chain chlorinated paraffins (SCCPs) are known to disturb thyroid hormone (TH) homeostasis in rodents. However, the mechanism remains to be fully characterized. In this study, male Sprague Dawley rats received SCCPs (0, 1, 10, or 100mg/kg/day) via gavage once a day for consecutive 28days. Plasma and hepatic TH concentrations, thyrocyte structure, as well as thyroid and hepatic mRNA and protein levels of genes associated with TH homeostasis were examined. Moreover, we performed molecular docking to predict interactions between constitutive androstane receptor (CAR), a key regulator in xenobiotic-induced TH metabolism, with different SCCP molecules. Exposure to SCCPs significantly decreased the circulating free thyroxine (T 4 ) and triiodothyronine (T 3 ) levels, but increased thyroid-stimulating hormone (TSH) levels by a feedback mechanism. Decreased hepatic T 4 and increased hepatic T 3 levels were also seen after 100mg/kg/day SCCPs exposure. SCCPs didn't show any significant effects on the expression of thyroid TH synthesis genes or thyrocyte structure. However, stimulation effects were observed for mRNA and protein levels of hepatic uridine diphosphoglucuronosyl transferase (UGT) 1A1 and organic anion transporter 2, suggesting an accelerated TH metabolism in rat liver. The increased cytochrome P450 2B1 but not 1A1 mRNA and protein levels indicated that the CAR signaling was activated by SCCPs exposure. According to docking analysis, SCCPs form hydrophobic interactions with CAR and the binding affinity shows dependency on chlorine content. Overall, our data showed that CAR implicated enhancement of hepatic TH influx and degradation could be the main cause for SCCPs induced TH deficiency in male rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats.

Science.gov (United States)

Linden, Melissa A; Meers, Grace M; Ruebel, Meghan L; Jenkins, Nathan T; Booth, Frank W; Laughlin, M Harold; Ibdah, Jamal A; Thyfault, John P; Rector, R Scott

2013-05-01

Physical activity-induced prevention of hepatic steatosis is maintained during short-term (7-day) transitions to an inactive state; however, whether these protective effects are present under a longer duration of physical inactivity is largely unknown. Here, we sought to determine whether previous physical activity had protective effects on hepatic steatosis and metabolic health following 4 wk of physical inactivity. Four-week old, hyperphagic, male Otsuka Long-Evans Tokushima fatty (OLETF) rats were randomly assigned to either a sedentary group for 16 wk (OLETF-SED), given access to running wheels for 16 wk with wheels locked 5 h (OLETF-WL5hr) or given access to running wheels for 12 wk with wheels locked 4 wk (OLETF-WL4wk) prior to death. Four weeks of physical inactivity caused hepatic steatosis development, but liver triglycerides remained 60% lower than OLETF-SED (P inactivity, whereas markers of fatty acid uptake and lipogenesis remained relatively suppressed following 4 wk of inactivity. In addition, 4 wk of inactivity caused a complete loss of activity-induced increases in serum IL-6 and reductions in regulated upon activation, normal T-cell expressed, and secreted (RANTES), and a partial loss in reductions in leptin, monocyte chemoattractant protein-1, and TNF-α. In conclusion, 4 wk of physical inactivity does not result in a complete loss in physical activity-induced benefits but does cause deterioration in the liver phenotype and overall metabolic health in hyperphagic OLETF rats.

miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model.

Science.gov (United States)

Su, Song; Luo, De; Liu, Xiangdong; Liu, Jiang; Peng, Fangyi; Fang, Cheng; Li, Bo

2017-10-31

A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir- miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir- miR-494 , and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H 2 O 2 -induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H 2 O 2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir- miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats ( P <0.05 or 0.01). After H 2 O 2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group ( P <0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor ( P <0.01). Moreover, HIRI + agomir- miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN , leading to the activation of PI3K/AKT signaling pathway. © 2017 The Author(s).

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

NARCIS (Netherlands)

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P. J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a

Acute and perinatal-programming effects of a fat-rich diet on rat muscle mitochondrial function and hepatic lipid accumulation

DEFF Research Database (Denmark)

Hellgren, Lars; Jensen, Runa I.; Waterstradt, Michelle S. G.

2014-01-01

respiratory control ratio with pyruvate, increased post weaning (p hepatic steatosis......Objective. Maternal high-fat intake during pregnancy may have long-term consequences in the offspring. Since this might relate to the capacity of mitochondrial metabolic adaptation and hepatic lipid metabolism, we investigated how maternal high-fat intake affected mitochondrial function and hepatic...... steatosis in the offspring. Design. Sprague–Dawley rats were fed a high-fat (20% w/w) or a control diet (chow, C) from 10 days before pregnancy and throughout lactation. At weaning the litters were split into two groups; one was continued on the maternal diet and the other was fed low-fat chow. Sample...

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

Energy Technology Data Exchange (ETDEWEB)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); Alegret, Marta; Merlos, Manuel; Roglans, Nuria [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB - Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain; Laguna, Juan C., E-mail: jclagunae@ub.edu [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB -Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain

2011-02-15

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid {beta}-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid {beta}-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

International Nuclear Information System (INIS)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S.; Alegret, Marta; Merlos, Manuel; Roglans, Nuria; Laguna, Juan C.

2011-01-01

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights: �

NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency

Directory of Open Access Journals (Sweden)

G. P. Kopylchuk

2015-02-01

Full Text Available The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADН is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences­ of energy exchange in the toxic hepatitis, induced on the background of protein deficiency.

Grape Seed oil as Anti hepatic and Anti renal Dysfunction agent in Paracetamol Administrated Rats

International Nuclear Information System (INIS)

Farag, M.F.; Osman, N.N.; Darwish, M.M.

2010-01-01

The protection conferred by dietary grape seed oil (GSO) against paracetamol (PCL)-induced liver and kidney dysfunction have been evaluated in adult male albino Wistar rats. The animals (180-200 g) were randomly divided into four groups of seven rats each. Group l: normal control, group II: animals received GSO (3.7 g Kg-1 body wt/day orally), group III: animals received PCL (4 g Kg-1 body wt/day orally) and group IV: animals received PCL plus GSO. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), urea (U), creatinine (Cr) and albumin (A) levels in serum and blood urea nitrogen (BUN) were measured. In addition, the levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of superoxide dismutase (SOD) and catalase (CAT) in the liver and kidney homogenates were chosen for assessing. The PCL induced a significant elevation in the serum AST, ALT, AP and GGT. Moreover, a significant increase in serum U, Cr, A and BUN were evident. Furthermore, a significant rise in TBARS, while a significant declined activity of SOD and CAT and GSH content in liver and kidney homogenates were also observed. Oral administration of GSO resulted in a significant reduction in liver and kidney markers in serum, BUN as well hepatic and renal TBARS accompanied by a significant improvement in the tissue antioxidants and A, when compared with PCL damaged rats. It was suggested that GSO has potent hepatic and renal protective effects against the oxidative damage induced in rats due to PCL treatment, perhaps by its antioxidative effects hence eliminating the deleterious effects of PCL.

The Levels Of Cytokines And S 100β Which Associated With The Pathogenesis Of Hepatic Encephalopathy In Rats: Role Of Lactulose And N-Acetylcysteine In Its Treatment

International Nuclear Information System (INIS)

Heibashy, M.I.A.; Mazen, G.M.A.; Ibrahim, M.A.

2012-01-01

Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure. Recently, it has been reported that pro inflammatory cytokines are involved in the pathogenesis of brain oedema during HE. This study was conducted to elucidate the changes of plasma and brain pro inflammatory cytokines in encephalopathy rats and to evaluate the hepato-protective activity of lactulose or N-acetylcysteine against thioacetamide (TAA) induced hepatopathy in rats. Acute hepatic encephalopathy (HE) in rats was induced by intraperitoneal injection of thioacetamide in 24 hours intervals for two consecutive days. The obtained results revealed significant increase (P<0.05) in liver function tests (ALT, AST, ALP, bilirubin), ammonia, nitric oxide and total oxidant capacity (TOC) in TAA rats than those in control ones. Brain water content was significantly elevated in TAA rats as compared with the control. In addition, the levels of pro inflammatory cytokines (IL-1Β, IL-6, TNF-α) in both serum and brain were significantly increased associated with a remarkable elevation in the level of serum S 100β in TAA rats. On the other hand, induction of hepatic encephalopathy caused significant decrease (P<0.05) in total antioxidant capacity (TAC) levels. When HE rats group was treated with lactulose or N-acetylcysteine, considerable amelioration effects in all previous studied parameters were pronounced dependent on certain mechanisms

Intracellular mechanism of action of sympathetic hepatic nerves on glucose and lactate balance in perfused rat liver

NARCIS (Netherlands)

Ballé, C.; Beuers, U.; ENGELHARDT, R.; JUNGERMANN, K.

1987-01-01

In rat liver perfused in situ stimulation of the nerve plexus around the hepatic artery and the portal vein caused an increase in glucose output and a shift from lactate uptake to output. The effects of nerve stimulation on some key enzymes, metabolites and effectors of carbohydrate metabolism were

A diet high in α-linolenic acid and monounsaturated fatty acids attenuates hepatic steatosis and alters hepatic phospholipid fatty acid profile in diet-induced obese rats.

Science.gov (United States)

Hanke, Danielle; Zahradka, Peter; Mohankumar, Suresh K; Clark, Jaime L; Taylor, Carla G

2013-01-01

This study investigated the efficacy of the plant-based n-3 fatty acid, α-linolenic acid (ALA), a dietary precursor of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for modulating hepatic steatosis. Rats were fed high fat (55% energy) diets containing high oleic canola oil, canola oil, a canola/flax oil blend (C/F, 3:1), safflower oil, soybean oil, or lard. After 12 weeks, C/F and weight-matched (WM) groups had 20% less liver lipid. Body mass, liver weight, glucose and lipid metabolism, inflammation and molecular markers of fatty acid oxidation, synthesis, desaturation and elongation did not account for this effect. The C/F group had the highest total n-3 and EPA in hepatic phospholipids (PL), as well as one of the highest DHA and lowest arachidonic acid (n-6) concentrations. In conclusion, the C/F diet with the highest content of the plant-based n-3 ALA attenuated hepatic steatosis and altered the hepatic PL fatty acid profile. © 2013 Published by Elsevier Ltd.

Effect of aubergine (Solanum melongena on serum and hepatic cholesterol and triglycerides in rats

Directory of Open Access Journals (Sweden)

Marcelo E Silva

1999-01-01

Full Text Available The present work reports the effect of aubergine extract on serum and hepatic cholesterol and triglycerides levels in adult rats. Fisher rats were divided into three groups: the first one received a normolipidic diet and water , serving as a control; the other two received a hypercholesterolaemic diet with 30% vegetable oil and 1% cholesterol, one of these being given water while the other was given an aubergine extract. After 28 days the animals were sacrificed and serum and hepatic cholesterol and triglycerides levels were assessed. The obtained results indicated that under the experimental conditions employed, the aubergine extract increased serum and decreased hepatic cholesterol and had little or no effect on both serum and hepatic triglycerides.A beringela (Solanum melongena tem sido apontada como possuidora da capacidade de reduzir o colesterol sérico. O chá do vegetal vem sendo utilizado com este propósito, devido ao interesse na descoberta de formas alternativas para o controle da hipercolesterolemia. No presente trabalho testou-se o efeito do chá de beringela nos níveis séricos e hepáticos de colesterol e triglicerídeos em ratos adultos. Ratos Fisher foram divididos em três grupos: o primeiro recebeu dieta normolipídica ad libitum e água para beber, funcionando como controle; os outros dois receberam dieta hipercolesterolêmica com 30% de óleo vegetal e 1% de colesterol, sendo dada a um destes grupos água para beber, enquanto que o outro recebeu apenas chá de beringela. Após 28 dias os animais foram sacrificados e dosaram-se os níveis de colesterol e triglicerídeos séricos e hepáticos. Os resultados obtidos indicam que, nas condições experimentais utilizadas, o chá de beringela eleva o colesterol sérico, reduz o hepático e tem pouco ou nenhum efeito sobre os triglicerídeos, tanto séricos quanto hepáticos.

Ascorbic acid deficiency decreases hepatic cytochrome P-450, especially CYP2B1/2B2, and simultaneously induces heme oxygenase-1 gene expression in scurvy-prone ODS rats.

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Kobayashi, Misato; Hoshinaga, Yukiko; Miura, Natsuko; Tokuda, Yuki; Shigeoka, Shigeru; Murai, Atsushi; Horio, Fumihiko

2014-01-01

The mechanisms underlying the decrease in hepatic cytochrome P-450 (CYP) content in ascorbic acid deficiency was investigated in scurvy-prone ODS rats. First, male ODS rats were fed a diet containing sufficient ascorbic acid (control) or a diet without ascorbic acid (deficient) for 18 days, with or without the intraperitoneal injection of phenobarbital. Ascorbic acid deficiency decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial cytochrome oxidase (COX) complex IV subunit I protein, and simultaneously increased heme oxygenase-1 protein in microsomes and mitochondria. Next, heme oxygenase-1 inducers, that is lipopolysaccharide and hemin, were administered to phenobaribital-treated ODS rats fed sufficient ascorbic acid. The administration of these inducers decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial COX complex IV subunit I protein. These results suggested that the stimulation of hepatic heme oxygenase-1 expression by ascorbic acid deficiency caused the decrease in CYP content in liver.

Development of a New Technique for Reconstruction of Hepatic Artery during Liver Transplantation in Sprague-Dawley Rat.

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Xingmu Liu

Full Text Available Sleeve anastomosis is the most common technique used to rearterialize orthotopic liver transplants (OLT. However, this technique has a number of disadvantages, including difficulty of performance of the technique visually unaided. We herein describe a novel rearterialized OLT model in the rat.Forty-six male Sprague Dawley rats (300-400 g were used as donors and recipients. Based on Kamada's cuff technique, the new model involved performing a modified "sleeve" anastomosis between the celiac trunk of the donor and common hepatic artery of the recipient to reconstruct blood flow to the hepatic artery. An additional ten male Sprague Dawley rats underwent liver transplantation without artery reconstruction. Liver grafts were retrieved from the two groups and histological examination was performed following surgery.Total mean operating times were ~42 minutes for the donor liver extraction and 57 minutes for the recipient transplantation. Graft preparation took an additional 15 minutes and the time to fix the arterial bracket was ~3 minutes. During transplantation, the anhepatic phase lasted 18 ± 2.5 min and the artery reconstruction only required ~3 minutes. The patency rate was 94.44% and the 4-week survival rate was 90%. Histology indicated obvious fibrosis in the liver grafts without artery reconstruction, while normal histology was observed in the arterialized graft.This new method allows for the surgical procedure to be performed visually unaided with good survival and patency rates and represents an alternative model investigating OLT in rats.

Pathological research on acute hepatic and renal tissue damage in Wistar rats induced by cocoa

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Chiedozie Onyejiaka Ibegbulem

2016-01-01

Conclusions: The pattern of alanine aminotransferase activity being more active than aspartate aminotransferase one in serum appeared to correlate with the extent of disarrangement of hepatic tissue architecture. The experimental rat groups exhibited no hyperbilirubinemia. Also, diets containing processed cocoa bean and raw cocoa bean products did not substantially interfere with the capacity of the hepatocytes to biosynthesize plasma proteins and the functionality of renal tissues.

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

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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

Preventive and curative effects of Cocculus hirsutus (Linn. Diels leaves extract on CCl4 provoked hepatic injury in rats

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Lavanya Goodla

2017-12-01

Full Text Available The present study was designed to estimate the protective or curative potency of an extract from Cocculus hirsutus leaves against CCl4 intoxication via its antioxidant property in rats. Liver enzyme markers (SGOT, SGPT, ALP, LDH, and bilirubin and oxidative stress markers {lipid peroxidation (LPO, enzymatic antioxidants [superoxide dismutase, catalase and glutathione peroxidase] and non-enzymatic antioxidants [reduced glutathione, vitamin C and E]} were analyzed by spectrophotometry. Histopathological studies on hepatic tissue were also performed by the method of Hematoxylin and Eosin staining. Rats administrated with 30% CCl4 in olive oil intraperitoneally resulted in significant increase in the levels of SGOT, SGPT, ALP, LDH, and bilirubin compared to control rats. Significant elevation of hepatic LPO and depletion of enzymatic and non-enzymatic antioxidants levels were observed in CCl4 induced rats. When CCl4 induced rats were co-treated with C. hirsutus at doses of 250 and 500 mg/kg b·wt, all the altered levels of liver marker enzymes and oxidative stress markers were restored to near control values. Histopathological studies provided direct evidence of the hepatoprotective effect of C. hirsutus. In conclusion, extract from C. hirsutus could protect the liver from CCl4-induced oxidative damage, by scavenging the free radicals generated during the metabolism of CCl4. Keywords: Antioxidants, Carbon tetrachloride, Cocculus hirsutus, Hepatoprotective effect, Lipid peroxidation

Evaluated the Up –regulation in Gene ‎Expression of Hepatic Insulin Gene and ‎Hepatic Insulin Receptor Gene in Type 1 ‎Diabetic Rats Treated with Cuscuta chinesis ‎Lam.‎

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Fadia ‎ H. Al-Sultany

2018-02-01

Full Text Available         This research was conducted to study the hypoglycemic activity of C. chinesis Lam on type 1 diabetic disease and investigate the  molecular and histological mechanism of  its action .many parameters was investigated , Fasting blood glucose (FBG, Fasting serum insulin,Hepatic Insulin Gene Expression, pancreas Insulin Gene Expression ,Hepatic Insulin  Receptors Gene expression  and histological sections of pancrease and liver.54 Rattus rattus male rats weighting(180 -200g were divided into 3 groups: A normal control daily administrated with Dw, B Diabetic control daily administrated with Dw  and C  diabetic group daily administrated with 400 mg/Kg body weight of C. chinesis  Lam. methanolic extract, each group consisted of  18 rats and further divided into (3 sub- groups 1 ,2  and 3. According to the period of administration  30, 60 and  90 days respectively. The results showing  the daily administration of 400 mg/Kg body weight of C. chinesis  Lam. methanolic extract for 60 day causing significance  decrease  in FBG and In the other hand each of fasting serum insulin, hepatic Insulin gene expression,pancreas Insulin gene expression and hepatic Insulin receptor gene expression was increased in group C in compare to B group and return all studied parameters involving pancrease and liver texture to the normal state ,which were statically morphologically  not appeared any significant difference from A group .this study concluded that the daily administration type 1 diabetic rats with 400 mg/Kg body weight of C. chinesis  Lam. extract for 60 day was return  fasting serum insulin and FBG to normal value by  upregulated  the gene expression of hepatic INS Gene ,INSR gene , pancreas INS Gene ,regenerate pancreatic beta- cell and returnthe texture of both liver and pancrease to the normal state

Inhibitory effect of tanshinone IIA on rat hepatic stellate cells.

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Ya-Wei Liu

Full Text Available Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation.The cell line of rat hepatic stellate cells (HSC-T6 was stimulated with lipopolysaccharide (LPS (100 ng/ml. Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM, then induced by LPS (100 ng/ml. NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38. Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells.All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells.Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.

Neonatal Persistent Exposure to 6-Propyl-2-thiouracil, a Thyroid-Disrupting Chemical, Differentially Modulates Expression of Hepatic Catalase and C/EBP-β in Adult Rats.

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Bunker, Suresh Kumar; Dandapat, Jagneshwar; Sahoo, Sunil Kumar; Roy, Anita; Chainy, Gagan B N

2016-02-01

Persistent exposure of rats to 6-propyl-2-thiouracil (PTU) from birth resulted in decreases in plasma thyroid hormone (TH) levels and hepatic expression of catalase and CCAAT enhancer binding protein β (C/EBP-β). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-β showed an augmentation in the methylation level along with a change in methylation pattern of CpG islands in response to PTU treatment. PTU withdrawal on 30 days of birth restored TH levels and C/EBP-β to control rats in adulthood. Although catalase expression was restored to some extent in adult rats in response to PTU withdrawal, a permanent change in its promoter CpG methylation pattern was recorded. The results suggest that downregulation of adult hepatic catalase gene in response to persistent neonatal PTU exposure may not solely be attributed to thyroid-disrupting properties of PTU. It is possible that besides thyroid-disrupting behavior, PTU may impair expression of hepatic catalase by altering methylation pattern of its promoter. © 2015 Wiley Periodicals, Inc.

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

Effects of lornoxicam and intravenous ibuprofen on erythrocyte deformability and hepatic and renal blood flow in rats.

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Arpacı, Hande; Çomu, Faruk Metin; Küçük, Ayşegül; Kösem, Bahadır; Kartal, Seyfi; Şıvgın, Volkan; Turgut, Hüseyin Cihad; Aydın, Muhammed Enes; Koç, Derya Sebile; Arslan, Mustafa

2016-01-01

Change in blood supply is held responsible for anesthesia-related abnormal tissue and organ perfusion. Decreased erythrocyte deformability and increased aggregation may be detected after surgery performed under general anesthesia. It was shown that nonsteroidal anti-inflammatory drugs decrease erythrocyte deformability. Lornoxicam and/or intravenous (iv) ibuprofen are commonly preferred analgesic agents for postoperative pain management. In this study, we aimed to investigate the effects of lornoxicam (2 mg/kg, iv) and ibuprofen (30 mg/kg, iv) on erythrocyte deformability, as well as hepatic and renal blood flows, in male rats. Eighteen male Wistar albino rats were randomly divided into three groups as follows: iv lornoxicam-treated group (Group L), iv ibuprofen-treated group (Group İ), and control group (Group C). Drug administration was carried out by the iv route in all groups except Group C. Hepatic and renal blood flows were studied by laser Doppler, and euthanasia was performed via intra-abdominal blood uptake. Erythrocyte deformability was measured using a constant-flow filtrometry system. Lornoxicam and ibuprofen increased the relative resistance, which is an indicator of erythrocyte deformability, of rats (P=0.016). Comparison of the results from Group L and Group I revealed no statistically significant differences (P=0.694), although the erythrocyte deformability levels in Group L and Group I were statistically higher than the results observed in Group C (P=0.018 and P=0.008, respectively). Hepatic and renal blood flows were significantly lower than the same in Group C. We believe that lornoxicam and ibuprofen may lead to functional disorders related to renal and liver tissue perfusion secondary to both decreased blood flow and erythrocyte deformability. Further studies regarding these issues are thought to be essential.

Hepatic macrophage complement receptor clearance function following injury.

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Cuddy, B G; Loegering, D J; Blumenstock, F A; Shah, D M

1986-03-01

Previous work has demonstrated that in vivo hepatic macrophage complement receptor clearance function is depressed following thermal injury. The present study was carried out to determine if complement receptor function depression is associated with other states of depressed host defense. Hepatic complement receptor clearance function was determined from the hepatic uptake of rat erythrocytes coated with antierythrocyte IgM (EIgM) in rats. Receptor function was determined following cannulation of a carotid artery, laparotomy plus enterotomy, hemorrhagic shock, trauma, thermal injury, acute bacteremia, acute endotoxemia, and injection of erythrocyte stroma, gelatinized lipid emulsion, or colloidal carbon. Hepatic uptake of EIgM was depressed following each of these experimental interventions except arterial cannulation. This effect was shown not to be due to a decrease in hepatic blood flow or depletion of complement and was therefore due to a depression in hepatic macrophage complement receptor clearance function. Thus, impairment of hepatic macrophage complement receptor function is associated with several states of depressed host defense.

Induction of hepatic aryl hydrocarbon hydroxylase and epoxide hydrase in Wistar rats pretreated with oral methadone hydrochloride.

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Bellward, G D; Gontovnick, L S; Otten, M

1977-01-01

Methadone-HCl added to the drinking water of adult female Wistar rats for 4 weeks produced an increase in the aryl hydrocarbon hydroxylase activity of the hepatic microsomal fraction to 222% of control levels. No change was seen in epoxide hydrase activity. In contrast, when male rats were treated similarly, there was an increase in epoxide hydrase activity to 212% of controls with no change in aryl hydrocarbon hydroxylase activity. No such changes were observed when the subcutaneous route of administration or chronic, low-dose, intraperitoneal injections were used. There were no differences in hepatic cytochrome P-450 or protein concentrations in treated animals as compared to their respective control groups. Control studies were carried out with quinine sulfate in the drinking water to decrease water intake to the level of the methadone-treated group. No elevation in either enzyme activity occurred in this control group. Similarly, paired-feeding studies showed the elevation of enzyme activity to be due to the methadone, not food deprivation. The effects of concurrent therapy of methadone with phenobarbital sodium or 3-methylcholanthrene were compared.

Activation and detoxification metabolism of urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone by rat and mouse hepatic microsomes.

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Stiborova, Marie; Cechova, Tereza; Borek-Dohalska, Lucie; Moserova, Michaela; Frei, Eva; Schmeiser, Heinz H; Paca, Jan; Arlt, Volker M

2012-01-01

2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. Understanding which enzymes are involved in metabolism of these toxicants is important in the assessment of individual susceptibility. Here, metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes containing cytochromes P450 (CYPs), their reductase (NADPH:CYP reductase), and NADH:cytochrome b5 reductase was investigated under anaerobic and aerobic conditions. In addition, using the same microsomal systems, 2-NBA and 3-NBA were evaluated to be enzymatically activated under anaerobic conditions to species generating 2-NBA- and 3-NBA-derived DNA adducts. High performance liquid chromatography (HPLC) with ultraviolet (UV) detection was employed for the separation and characterization of 2-NBA and 3-NBA metabolites formed by hepatic microsomes of rats and mice under the anaerobic and aerobic conditions. Microsomal systems isolated from the liver of the control (untreated) rats and rats pretreated with Sudan I, β-naphthoflavone (β-NF), phenobarbital (PB), ethanol and pregnenolon 16α-carbonitrile (PCN), the inducers of cytochromes P450 (CYP) 1A1, 1A1/2, 2B, 2E1 and 3A, respectively, were used in this study. Microsomes of mouse models, a control mouse line (wild-type, WT) and Hepatic Cytochrome P450 Reductase Null (HRN) mice with deleted gene of NADPH:CYP reductase in the liver, thus absenting this enzyme in their livers, were also employed. To detect and quantify the 2-NBA- and 3-NBA-derived DNA adducts, the 32P postlabeling technique was used. Both reductive metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), found to be formed predominantly under the anaerobic conditions, and two 3-NBA oxidative metabolites, whose structures have not yet been investigated, were formed by several microsomal systems used in the study. Whereas a 3-NBA reductive metabolite

Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats.

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Jiang, Shu-Jun; Dong, Hui; Li, Jing-Bin; Xu, Li-Jun; Zou, Xin; Wang, Kai-Fu; Lu, Fu-Er; Yi, Ping

2015-07-07

To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model. The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups (n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine (156 mg/kg per day) (berberine group) or metformin (184 mg/kg per day) (metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) (0.5 mg/kg per day) (AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested. The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator (TORC)2 was observed by immunohistochemical staining. Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Berberine upregulated protein expression of liver kinase (LK)B1, AMP-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK). The level of phophorylated TORC2 (p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues. Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2

The effects of herbal composition Gambigyeongsinhwan (4) on hepatic steatosis and inflammation in Otsuka Long-Evans Tokushima fatty rats and HepG2 cells.

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Yoon, Seolah; Kim, Jeongjun; Lee, Hyunghee; Lee, Haerim; Lim, Jonghoon; Yang, Heejeong; Shin, Soon Shik; Yoon, Michung

2017-01-04

Hepatic steatosis has risen rapidly in parallel with a dramatic increase in obesity. The aim of this study was to determine whether the herbal composition Gambigyeongsinhwan (4) (GGH(4)), composed of Curcuma longa L. (Zingiberaceae), Alnus japonica (Thunb.) Steud. (Betulaceae), and the fermented traditional Korean medicine Massa Medicata Fermentata, regulates hepatic steatosis and inflammation. The effects of GGH(4) on hepatic steatosis and inflammation in Otsuka Long-Evans Tokushima fatty (OLETF) rats and HepG2 cells were examined using Oil red O, hematoxylin and eosin, and toluidine blue staining, immunohistochemistry, quantitative real-time polymerase chain reaction, and peroxisome proliferator-activated receptor α (PPARα) transactivation assay. Administration of GGH(4) to OLETF rats improved hepatic steatosis and lowered serum levels of alanine transaminase, total cholesterol, triglycerides, and free fatty acids. GGH(4) increased mRNA levels of fatty acid oxidation enzymes (ACOX, HD, CPT-1, and MCAD) and decreased mRNA levels of lipogenesis genes (FAS, ACC1, C/EBPα, and SREBP-1c) in the liver of OLETF rats. In addition, infiltration of inflammatory cells and expression of inflammatory cytokines (CD68, TNFα, and MCP-1) in liver tissue were reduced by GGH(4). Treatment of HepG2 cells with a mixture of oleic acid and palmitoleic acid induced significant lipid accumulation, but GGH(4) inhibited lipid accumulation by regulating the expression of hepatic fatty acid oxidation and lipogenic genes. GGH(4) also increased PPARα reporter gene expression. These effects of GGH(4) were similar to those of the PPARα activator fenofibrate, whereas the PPARα antagonist GW6471 reversed the inhibitory effects of GGH(4) on lipid accumulation in HepG2 cells. These results suggest that GGH(4) inhibits obesity-induced hepatic steatosis and that this process may be mediated by regulation of the expression of PPARα target genes and lipogenic genes. GGH(4) also suppressed obesity

End product inhibition of hepatic 25-hydroxyvitamin D production in the rat: specificity and kinetics

International Nuclear Information System (INIS)

Milne, M.L.; Baran, D.T.

1985-01-01

The role of vitamin D metabolites in the regulation of hepatic 25-hydroxyvitamin D production was investigated by examining the effects of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D on the synthesis of [25- 3 H]hydroxyvitamin D by rachitic rat liver homogenates. Production of [25- 3 H]hydroxyvitamin D was inhibited by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, but not by 24,25-dihydroxyvitamin D. 25-Hydroxyvitamin D increased the Km of the vitamin D-25-hydroxylase enzyme(s), while 1,25-dihydroxyvitamin D decreased the Vmax with a Ki of 88.7 ng/ml. Inhibition of hepatic 25-hydroxyvitamin D production by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may be another control mechanism to regulate circulating vitamin D levels

Voluntary Ingestion of Natural Cocoa Extenuated Hepatic Damage in Rats with Experimentally Induced Chronic Alcoholic Toxicity

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Godwin Sokpor

2012-05-01

Full Text Available Background: Chronic ethanol ingestion causes hepatic damage imputable to an increasedoxidative stress engendered by alcoholic toxicity. Polyphenols in cocoa have antioxidant properties, and natural cocoa powder (NCP contains the highest levels of total antioxidant capacity when compared to all other kinds of edible cocoa products. This study tested the hypothesis that dietary supplementation with NCP mitigates hepatic injury resulting from chronic ethanol consumption. Three groups of eight randomized Sprague-Dawley rats were fed standardrat food and treated daily for 12 weeks as follows: (i the Ethanol-water group was given unrestricted access to 40% (v/v ethanol for 12 hours (at night followed by water for the remaining 12 hours (daytime, (ii the Ethanol-cocoa group had similarly unrestricted access to 40% ethanol for 12 hours followed by 2% (w/v NCP for 12 hours, and (iii the control group was not given alcohol and had unrestricted access to only water which was synchronously replenished every 12 hours as it was for the ethanol treated animals.Results: Qualitative structural liver damage evidenced by hepatocyte cytoplasmic fatty accumulation, nuclear alterations, and disruption of general liver micro-architecture, was severe in the ethanol-water group when compared with the ethanol-cocoa group of rats. Design-based stereologic assessment yielded a significantly greater volume (Tukey’s HSD, p = 0.0005 ofundamaged hepatocytes (9.61 ml, SD 2.18 ml in the ethanol-cocoa group as opposed to theethanol-water group of rats (2.34 ml, SD 1.21 ml. Control rats had 10.34 ml (SD 1.47 ml of undamaged hepatocytes, and that was not significantly greater (Tukey’s HSD, p=0.659 than the value for the ethanol-cocoa group of rats. Relative to controls, therefore, histomorphometryFunctional Foods in Health and Disease 2012, 2(5:166- 187 showed 93% hepatocyte preservation from alcoholic injury in rats that voluntarily imbibed NCP suspension compared with 23% in

Comparative assessment of onion and garlic extracts on endogenous hepatic and renal antioxidant status in rat.

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Suru, Stephen M; Ugwu, Chidiebere E

2015-07-01

Despite growing claims of functional health benefits in folkloric medicine, the safety of chronic/elevated intakes of onion and garlic cannot be assumed. Therefore, this study assesses oral administration of varied doses of onion and garlic on some biomarkers of hepatic and renal functions in rats. Animals were divided into five groups: control group received vehicle and extract-treated groups received varied doses of onion or garlic extract (0.5 mL and 1.0 mL/100 g bwt/day) for 6 weeks. Both doses of onion caused marked (pgarlic elicited similar trend except in hepatic CAT, renal SOD and GST levels. A high dose of garlic only caused marked (pgarlic significantly (pgarlic, while high dose of garlic elicited pro-oxidant conditions.

Hepatic expression of spermatogenic genes and their transiently remarkable downregulations in Wistar-Kyoto rats in response to lead-nitrate administration: strain-difference in the gene expression patterns.

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Nemoto, Kiyomitsu; Ito, Sei; Yoshida, Chiaki; Miyata, Misaki; Kojima, Misaki; Degawa, Masakuni

2011-06-01

Administration of lead ion (Pb) to rats and mice affects hepatic functions such as the induction of hepatic cell proliferation and upregulation of cholesterol biosynthesis. To identify the genes for which expression changes in response to Pb-administration, we analyzed hepatic gene expression patterns in stroke-prone spontaneously hypertensive rat (SHRSP), its normotensive control, Wistar-Kyoto rat (WKY), and Spraque-Dawley (SD) rat strains, 3, 6, and 12 hr later after single i.v. injection of lead nitrate (LN) at a dose of 100 µmol using a DNA microarray technique. The data analysis demonstrated that the expression of a great number of genes was transiently and remarkably downregulated 3 hr after LN-injection, and then recovered to control levels only in LN-injected WKY. These normal hepatic expression levels in WKY and SHRSP were much higher than those in SD rats. Furthermore, most of these genes were ones thought to be expressed specifically in the spermatids and/or testes; i.e. genes encoding protamin 1, transition protein 1, and transition protein 2. These findings suggest that the regulation system common to expression of all of these genes could be a target site of Pb-toxic action, at least, in the liver of WKY, and that this system might be similar to the system essential for spermatogenesis, especially spermiogenesis, in the testis. In addition, it appears that clarifying the cause of the difference between the systems of WKY and SHRSP might aid in identifying the pathologic genes in SHRSP. Finally, it will be an important to clarify how the products of the genes related to spermatogenesis, including spermiogenesis, are functional in the livers of WKY and SHRSP.

Melatonin protects against lead-induced hepatic and renal toxicity in male rats

International Nuclear Information System (INIS)

El-Sokkary, Gamal H.; Abdel-Rahman, Gamal H.; Kamel, Esam S.

2005-01-01

The present study was designed to investigate the potential protective effect of melatonin against the hepatic and renal toxicity of lead in male rats. Three groups of animals were used in this study (control, lead acetate-treated (100 mg/kg), and lead acetate plus melatonin (10 mg/kg) for 30 days. Levels of lipid peroxidation (LPO) products, superoxide dismutase (SOD) activity, total glutathione (GSH), histopathological changes in the liver and kidneys were investigated. In addition, nuclear area (NA), nuclear volume (NV) and the ratio of nuclear volume/cellular volume (N/C) were measured in the liver. The results revealed increased LPO and decreased SOD, GSH, NA, NV and N/C in the studied organs of lead-treated rats. Histopathological observations showed severe damage in the liver and kidneys. Melatonin co-treatment to the lead-administered rats attenuated the increase of LPO and restored the activity of SOD and levels of GSH as well as the mean values of NA, NV and N/C. Also, the morphological damage in the liver and kidneys was reduced and the tissues appeared like those of controls. The present study suggests that melatonin may be useful in combating free radical-induced damage due to lead toxicity

Ginger extract modulates Pb-induced hepatic oxidative stress and expression of antioxidant gene transcripts in rat liver.

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Mohamed, Omnia Ismail; El-Nahas, Abeer Fekry; El-Sayed, Yasser Said; Ashry, Khaled Mohamed

2016-07-01

Spices and herbs are recognized sources of natural antioxidants that can protect from oxidative stress, thus play an important role in chemoprevention of liver diseases. Ginger is used worldwide primarily as a spicy condiment. This study evaluated the ability of ginger extract (GE) to ameliorate oxidative-hepatic toxicity induced by lead acetate (PbAc) in rats. Five groups of animals were used: group I kept as control; groups II, IV, and V received PbAc (1 ppm in drinking water daily for 6 weeks, and kept for an additional 2 weeks without PbAc exposure); group III treated orally with GE (350 mg/kg body weight, 4 d per week) for 6 weeks; group IV (protective) received GE for 2 weeks before and simultaneously with PbAc; and group V (treatment) received GE for 2 weeks after PbAc exposure. GC-MS analysis of GE revealed its content of gingerol (7.09%), quercetin (3.20%), dl-limonene (0.96%), and zingiberene (0.18%). Treatment of PbAc-treated rats with GE has no effect on hepatic Pb concentrations. However, it maintained serum aspartate aminotransferase level, increased hepatic glutathione (157%), glutathione S-transferase (GST) (228%), glutathione peroxidase (GPx) (138%) and catalase (CAT) (112%) levels, and reduced hepatic malondialdehyde (80%). Co-treatment of PbAc group with GE upregulated mRNA expression of antioxidant genes: GST-α1 (1.4-fold), GPx1 (1.8-fold), and CAT (8-fold), while post-treatment with GE upregulated only mRNA expression of GPx1 (1.5-fold). GE has an antioxidant protective efficacy against PbAc-induced hepatotoxicity, which appears more effective than its therapeutic application. However, the changes in antioxidant gene expression were not reflected at the protein level.

Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease.

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Yamamoto, Hiroya; Kanno, Keishi; Ikuta, Takuya; Arihiro, Koji; Sugiyama, Akiko; Kishikawa, Nobusuke; Tazuma, Susumu

2016-05-01

We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Differential effects of high-carbohydrate and high-fat diets on hepatic lipogenesis in rats.

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Ferramosca, Alessandra; Conte, Annalea; Damiano, Fabrizio; Siculella, Luisa; Zara, Vincenzo

2014-06-01

Hepatic fatty acid synthesis is influenced by several nutritional and hormonal factors. In this study, we have investigated the effects of distinct experimental diets enriched in carbohydrate or in fat on hepatic lipogenesis. Male Wistar rats were divided into four groups and fed distinct experimental diets enriched in carbohydrates (70% w/w) or in fat (20 and 35% w/w). Activity and expression of the mitochondrial citrate carrier and of the cytosolic enzymes acetyl-CoA carboxylase and fatty acid synthetase were analyzed through the study with assessments at 0, 1, 2, 4, and 6 weeks. Liver lipids and plasma levels of lipids, glucose, and insulin were assayed in parallel. Whereas the high-carbohydrate diet moderately stimulated hepatic lipogenesis, a strong inhibition of this anabolic pathway was found in animals fed high-fat diets. This inhibition was time-dependent and concentration-dependent. Moreover, whereas the high-carbohydrate diet induced an increase in plasma triglycerides, the high-fat diets determined an accumulation of triglycerides in liver. An increase in the plasmatic levels of glucose and insulin was observed in all cases. The excess of sucrose in the diet is converted into fat that is distributed by bloodstream in the organism in the form of circulating triglycerides. On the other hand, a high amount of dietary fat caused a strong inhibition of lipogenesis and a concomitant increase in the level of hepatic lipids, thereby highlighting, in these conditions, the role of liver as a reservoir of exogenous fat.

Garlic and Resveratrol attenuate diabetic complications, loss of β-cells, pancreatic and hepatic oxidative stress in streptozotocin-induced diabetic rats

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Gagandeep Kaur

2016-10-01

Full Text Available Abstract:The study was aimed at finding the effect of garlic and resveratrol on loss of β-cells and diabetic complication in streptozotocin (STZ-induced Type-I diabetic rats. Rats were injected with single dose STZ (50mg/kg, i.p. for induction of type 1 diabetes (Dia and compared with control group. Rats from third (Dia+Gar, fourth (Dia+Resv and fifth (Dia+Met groups were fed raw garlic homogenate (250 mg/kg/day, resveratrol (25 mg/kg/day and metformin (500 mg/kg/day orally, respectively for a period of 4 weeks. Diabetic group had decreased serum insulin and hydrogen sulfide levels along with increased blood glucose and glycated hemoglobin, triglyceride, uric acid and nitric oxide levels. Significant (p<0.05 increase in pancreatic and hepatic TBARS, conjugated dienes, nitric oxide, and AGE level and significant (p<0.05 decrease in SOD, catalase, H2S, GSH level were observed in diabetic group. Administration of garlic, resveratrol and metformin significantly (p<0.05 normalized most of the altered metabolic and oxidative stress parameters as well as histopathological changes. Administration of garlic, resveratrol and 9metformin in diabetic rat decreases pancreatic β-cell damage and hepatic injury. Our data concluded that administration of garlic showed more promising effect in terms of reducing oxidative stress and pathological changes when compared to resveratrol and metformin groups.

Long-term effect of medium-chain triglyceride on hepatic enzymes catalyzing lipogenesis and cholesterogenesis in rats

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Takase, Sachiko; Morimoto, Ayami; Nakanishi, Mayumi; Muto, Yasutoshi.

1977-01-01

This study was conducted to investigate the long-term effect of dietary medium-chain triglyceride (MCT) as compared with that of corn oil feeding on lipid metabolism in rats. Both serum cholesterol and triglyceride levels in MCT-fed rats showed significant decrease during the experimental period of eight weeks, although liver cholesterol and triglyceride contents were not distinguishable between the two groups. Significant elevation of the activity of lipogenic enzymes, such as fatty acid synthetase (FAS) and malic enzyme (ME) of the liver, was observed in MCT-fed rats without any fat accumulation of the liver (fatty liver). The increase of lipogenic enzyme activity was accompanied by a significant reduction of essential fatty acids (EFA) such as 18:2 (ωsigma) and 20:4 (ωsigma) in total liver lipid. In contrast, hepatic β-hydroxy-β-methylglutaryl CoA(HMG-CoA) reductase activity was significantly decreased in MCT-fed rats, that would play an important role in achieving hypocholesterolemia. From these results obtained in a long-term experiment, it is concluded that exogenous MCT depresses the key enzyme catalyzing cholesterol synthesis with a concomitant elevation of lipogenic enzyme activity in the rat liver. (auth.)

Association between hepatic cholesterol and oleic acid in the liver of rats treated with partially hydrogenated vegetable oil

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Gabriela Salim Ferreira de Castro

2012-02-01

Full Text Available OBJECTIVE: The aim of the present study was to investigate the lipid profiles of the hepatic and adipose tissues of Wistar rats treated for 21 days with a diet high in saturated fat (high saturated fat, n=6 or high in hydrogenated fat, that is, having 50% partially hydrogenated vegetable oil in its composition (high hydrogenated fat, n=6, and compare them to those of a control group (control group, n=6. METHODS: Adipose tissue and total hepatic fat were higher in the saturated fat group than in the hydrogenated fat group. Hepatic lipid peroxidation was greatest in the saturated fat group, with consequent lower hepatic vitamin E and A levels. In contrast, serum vitamin A was highest in the saturated fat group. Analysis of hepatic lipid fractions found more cholesterol and less high density lipoprotein-cholesterol in the hydrogenated fat group. The hydrogenated fat group had the highest levels of triacylglycerols, followed by the saturated fat group. RESULTS: Significant amounts of trans fatty acids were detected in the hepatic and adipose tissues of the hydrogenated fat group. Among the identified fatty acids, 18:1n9 had a higher positive association with hepatic cholesterol and triacylglycerols, and a higher negative association with high density lipoprotein-cholesterol. Partially hydrogenated vegetable oil promotes greater accumulation of cholesterol and triacylglycerols in the liver than saturated fats. CONCLUSION: Trans fatty acids were incorporated into hepatocytes and adipocytes in a highly efficient manner.

Effect of trans-chalcone on hepatic IL-8 through the regulation of miR-451 in male rats

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Karimi-Sales Elham

2018-01-01

Full Text Available Objective. Trans-chalcone is a chalcone with hepatoprotective and anti-inflammatory effects. However, the mechanism of these positive effects, especially on miR-451 as an inflammatory regulator, is poorly understood. In this regard, this microRNA (miRNA acts by inhibition of hepatic interleukin-8 (IL-8 production in the liver which is one of the main proinflammatory cytokines. Th is study for the first time examined the effect of trans-chalcone on miR-451/IL-8 pathway. Methods. In present study, 21 male rats were randomly divided into 3 groups (n=7 per each group: control which received solvent (NS, groups 2 (N2T and 3 (N6T, which received transchalcone for 2 and 6 weeks, respectively. Hepatic level of miR-451 was measured by qRT-PCR. Serum levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST as well as hepatic level of IL-8 protein were measured. Results. Trans-chalcone decreased hepatic level of IL-8 protein and serum level of ALT aft er 2 weeks of treatment without significant change in hepatic miR-451. Moreover, it increased hepatic level of miR-451 and reduced hepatic IL-8 as well as AST and ALT aft er 6 weeks. Conclusion. Based on the results of present study, miR-451/IL-8 pathway is a possible mechanism for hepatoprotective action of trans-chalcone in long-term.

In vitro hepatic microsomal metabolism of meloxicam in koalas (Phascolarctos cinereus), brushtail possums (Trichosurus vulpecula), ringtail possums (Pseudocheirus peregrinus), rats (Rattus norvegicus) and dogs (Canis lupus familiaris).

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Kimble, B; Li, K M; Valtchev, P; Higgins, D P; Krockenberger, M B; Govendir, M

2014-04-01

Quantitative and qualitative aspects of in vitro metabolism of the non-steroidal anti-inflammatory drug meloxicam, mediated via hepatic microsomes of specialized foliage (Eucalyptus) eating marsupials (koalas and ringtail possums), a generalized foliage eating marsupial (brushtail possum), rats, and dogs, are described. Using a substrate depletion method, intrinsic hepatic clearance (in vitro Clint) was determined. Significantly, rates of oxidative transformation of meloxicam, likely mediated via cytochromes P450 (CYP), were higher in marsupials compared to rats or dogs. The rank order of apparent in vitro Clint was brushtail possums (n=3) (mean: 394μL/min/mg protein), >koalas (n=6) (50), >ringtail possums (n=2) (36) (with no significant difference between koalas and ringtail possums), >pooled rats (3.2)>pooled dogs (in which the rate of depletion, as calculated by the ratio of the substrate remaining was <20% and too slow to determine). During the depletion of meloxicam, at a first-order rate constant, 5-hydroxymethyl metabolite (M1) was identified in the brushtail possums and the rat as the major metabolite. However, multiple hydroxyl metabolites were observed in the koala (M1, M2, and M3) and the ringtail possum (M1 and M3) indicating that these specialized foliage-eating marsupials have diverse oxidation capacity to metabolize meloxicam. Using a well-stirred model, the apparent in vitro Clint of meloxicam for koalas and the rat was further scaled to compare with published in vivo Cl. The closest in vivo Cl prediction from in vitro data of koalas was demonstrated with scaled hepatic Cl(total) (average fold error=1.9) excluding unbound fractions in the blood and microsome values; whereas for rats, the in-vitro scaled hepatic Cl fu(blood, mic), corrected with unbound fractions in the blood and microsome values, provided the best prediction (fold error=1.86). This study indicates that eutherians such as rats or dogs serve as inadequate models for dosage

Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on hepatic steatosis in Zucker rats.

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Plaza-Diaz, Julio; Gomez-Llorente, Carolina; Abadia-Molina, Francisco; Saez-Lara, Maria Jose; Campaña-Martin, Laura; Muñoz-Quezada, Sergio; Romero, Fernando; Gil, Angel; Fontana, Luis

2014-01-01

We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Lepr(fa/fa) rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Lepr(fa/fa) rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Lepr(fa/fa) rats that received probiotics than in rats fed the placebo. Zucker-Lepr(fa/fa) rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Lepr(fa/fa) rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Lepr(fa/fa) rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Lepr(fa/fa) rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.

Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on hepatic steatosis in Zucker rats.

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Julio Plaza-Diaz

Full Text Available We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Lepr(fa/fa rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Lepr(fa/fa rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Lepr(fa/fa rats that received probiotics than in rats fed the placebo. Zucker-Lepr(fa/fa rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Lepr(fa/fa rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Lepr(fa/fa rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Lepr(fa/fa rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.

Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

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Yang, Tao; Liu, Shan; Wang, Chang-Hong; Tao, Yan-Yan; Zhou, Hua; Liu, Cheng-Hai

2015-10-10

Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. Copyright © 2015 Elsevier B.V. All rights reserved.

Viral persistence, liver disease and host response in Hepatitis C-like virus rat model

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Trivedi, Sheetal; Murthy, Satyapramod; Sharma, Himanshu

2018-01-01

The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could...... potentially provide useful surrogate models. We isolated a rodent hepacivirus (RHV) from wild rats (Rattus norvegicus), RHV-rn1, acquired the complete viral genome sequence and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein...... cleavage sites and secondary structures in the viral 5' and 3' UTRs. We used site-directed and random mutagenesis to determine that only the first of the two miR-122 seed sites in viral 5'UTR is required for viral replication and persistence in rats. Next, we used the clone derived virus progeny to infect...

Hepatic glycogen levels in female rats submitted to aquatic therapy after muscle disuse

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Jefferson Pacheco Amaral Fortes

2017-12-01

Full Text Available The aim of the present study was to analyse the changes in liver glycogen content in rats subjected to aquatic therapy post-disuse of the paw. 32 wistar adult female rats were equally divided: Control (C, kept in the cage for two weeks without interventions; Disuse (D had the right paw immobilized with hip extension, knee and plantar flexion for two weeks; Aquatic Therapy (AT underwent aquatic therapy with increments of 3 minutes daily for two weeks, totalizing 36 minutes of training; Disused Aquatic Therapy (DTA was first subjected to immobilization for two weeks and 24 hours after withdrawal of immobilization aquatic therapy was started for two more weeks, in same protocols of D and AT groups. At the end of the experiment, the animals were sacrificed, and tissues were dissected, weighed and stored. The liver tissues were referred analysis of glycogen content. It was observed that the blood glucose levels of the AT group (104 mg/dL were different from the C group (86 mg/dL; p = 0.0213. Regarding hepatic glycogen, the D (2.35mg±0.07 and AT (2.73mg±0.07 groups had hepatic glycogen reduction by 22% and 15%, relative to C (2.51mg±0.03; p <0.0001. The DTA group presented no differences when compared to the control, suggesting the normalization of the finding. Muscle disuse by two weeks promoted changes in glycogen levels, however, two weeks after disuse condition, the aquatic therapy were able to correct the energetic reserve in liver.

Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet.

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da Silva, Robin P; Leonard, Kelly-Ann; Jacobs, René L

2017-12-01

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague-Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

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Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

2017-08-01

The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.

Polyploidy Analysis and Attenuation of Oxidative Stress in Hepatic Tissue of STZ-Induced Diabetic Rats Treated with an Aqueous Extract of Vochysia rufa

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Izabela Barbosa Moraes

2015-01-01

Full Text Available Diabetes mellitus (DM is characterized by hyperglycemia and alterations in the metabolism of lipids, carbohydrates, and proteins. Due to its hypoglycemic effect Vochysia rufa is frequently used in Uberlandia, Brazil, to treat DM. Despite its popularity, there is little information about its effect on hepatic tissue. Therefore, we evaluated the histoarchitecture, oxidative stress parameters, and polyploidy of liver tissue from streptozotocin- (STZ- induced diabetic rats treated with aqueous extract of Vochysia rufa (AEV. Histology was determined by fixing the livers, processing, and staining with HE. Oxidative stress was determined by evaluating CAT, GPx, and SOD activity in liver homogenates and hepatic mitochondria fraction and by measuring GST, GSH levels and lipid peroxidation (MDA. Polyploidy was determined by subjecting isolated hepatocyte nuclei to flow cytometry. In the diabetic group, GST activity and GSH rates decreased whereas liver homogenate analysis showed that GPx, SOD activity and MDA increased. AEV treatment restored all parameters to normal levels. The oxidative stress analysis of hepatic mitochondria fraction showed similar results. Lower polyploid cell populations were found in the diabetic rat livers, even after glibenclamide treatment. Thus, AEV treatment efficiently reduced hepatic oxidative stress caused by STZ-induced diabetes and produced no morphological changes in the histological analysis.

Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats

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Idália M. B. Burlamaqui

2011-06-01

Full Text Available CONTEXT: Non-alcoholic fatty liver disease is characterized by lipid deposits in the hepatocytes and has been associated with obesity, dyslipidemia and type-2 diabetes. It is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance leading to hyperinsulinemia and increased production of inflammatory cytokines. Saturated fat promotes hypertriglyceridemia and hyperinsulinemia, reduces levels of high-density cholesterol and increases levels of low-density cholesterol, while polyunsaturated fat is associated with hypolipidemic, antiinflammatory and imunoregulating action. OBJECTIVE: To evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich diet in Wistar rats. METHODS: Twenty-two rats were distributed equally in two groups: GI - standard diet (Biobase Bio-tec Ratos e Camundongos® providing 3.000 kcal/kg and GII - hypercaloric and hyperlipidic diet providing 4.250 kcal/kg (ω-6:ω-3 = 3:1. The animals were euthanized after 23 weeks of experiment. The weight, biochemical parameters and hepatohistological changes were registered. RESULTS: Findings were submitted to variance analysis with the level of statistical significance at 5%. The average weight did not differ significantly between the groups at baseline (P = 0.711, but was greater in Group II by the end of the experiment (P = 0.000. The levels of triglycerides (P = 0.039, total cholesterol (P = 0.015 and HDL (P = 0.005 were higher in Group I than in Group II. Macrovesicular steatosis was significantly more common in Group II than in Group I (P = 0.03. CONCLUSION: Hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL.

A study on the Regenerative Effect of Platelets Rich Plasma on Experimentally Induced Hepatic Damage In Albino Rats.

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Shoeib, Heba Mamdoh; Keshk, Walaa Arafa; Foda, Abdallah Mahmoud; Abo El Noeman, Saad El-Deen Abd Elfatah

2018-02-14

Hepatic fibrosis is a worldwide health problem with significant morbidity and mortality. Currently, there is no effective therapy for hepatic fibrosis. So that the present study was aimed to evaluate the possible regenerative effect of Platelet-rich plasma (PRP) against thioacetamide (TAA) induced hepatic damage. Eighty albino rats were included; 40 were used for PRP preparation and 40 were randomly divided into four groups. Group I (control group); group II (PRP control); group III (TAA- intoxicated in a dose of 200 mg ∕ kg body weight/twice weekly for 7 weeks, intra-peritoneal and group IV (TAA-intoxicated+ PRP treated). Macrophage inflammatory protein-1α (MIP-1α) and cyclic adenosine monophosphate (cAMP) were immunoassayed in addition to peroxinitrite level, NADPH-quinine oxido-reductase-1 (NQO1) enzyme activity and liver function. PRP treatment showed significant improvement in hepatic function, decreased MIP-1α and peroxinitrite level. Meanwhile, significant increase in NQO1 enzyme activity and cAMP level were observed. The histopathological results confirmed the laboratory results with improvement of hepatic architecture except for some inflammatory cellular infiltrates. PRP has the ability to protect against TAA-induced liver damage possibly by improving redox status, liver histopathological architecture, disruption of the inflammatory and fibrotic response induced by TAA.

The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats

International Nuclear Information System (INIS)

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

Influence of zinc on the biokinetics of Zn-65 and hepatic trace elements of ethanol treated rats

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Dhawan, D.K.; Pathak, A.; Pathak, R.; Mahmood, A.

2002-01-01

Influence of zinc on the biokinetics of 65 Zn and hepatic trace elements of ethanol treated rats. The effect of zinc on the biokinetics of 65 Zn in liver and whole body and its relation to the hepatic levels of different elements was evaluated in male wistar rats under alcoholic conditions. The rats were segregated into four treatment groups viz., normal control, ethanol treated, zinc treated and combined zinc+ethanol treated. Animals were fed 3ml of 30% ethanol orally daily and zinc in the form of zinc sulfate (ZnSo 4 7H 2 O) was administrated to rats at a dose level of 227mg/L mixed in their drinking water for a total duration of 2 months. Whole body counting studies indicated that the Tb 1 i.e., the faster elimination of the radiotracer. On the contrary, Tb 2 i.e., the slower component was increased significantly following ethanol treatment. Percent uptake values of 65 Zn were found to be increased in liver, intestine, muscle and kidney and decreased in bone under alcoholic conditions. A significant elevation was noticed in in vitro uptake 65 Zn in ethanol treated animals. In the above said conditions, the values were reverted back to within normal limits upon zinc supplementation to these ethanol intoxicated animals, except in the case of in vitro 65 Zn uptake in liver where the uptake was further increased upon combined treatment. A significant decrease in zinc contents was noticed in ethanol treated rats, which however were raised to normal levels upon zinc supplementation. Copper levels, on the other hand, were found to be significantly enhanced in both ethanol fed and combined ethanol+zinc supplemented animals. Calcium levels were found to e significantly decreased in both ethanol and zinc treated rats, which however were further reduced upon zinc supplementation to ethanol fed rats. However, no significant change was observed in the concentrations of sodium and potassium in any of the treatment groups. Therefore, zinc appears to play a protective role by

EFFECT OF ETHANOL ON HEPATOBILIARY TRANSPORT OF CATIONIC DRUGS - A STUDY IN THE ISOLATED-PERFUSED RAT-LIVER, RAT HEPATOCYTES AND RAT MITOCHONDRIA

NARCIS (Netherlands)

STEEN, H; MEIJER, DKF; Merema, M.T.

The effect of ethanol on the hepatic uptake of various cationic drugs was studied in isolated perfused rat livers, isolated rat hepatocytes and isolated rat liver mitochondria. In isolated rat hepatocytes and in isolated perfused rat livers, the uptake of the model organic cation

Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

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Li, Songtao; Liao, Xilu; Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

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Songtao Li

Full Text Available BACKGROUND: Non-alcoholic fatty liver disease (NAFLD is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA, an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD-induced obese non-alcoholic fatty liver disease (NAFLD rat model. METHODOLOGY/PRINCIPAL FINDINGS: Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. CONCLUSIONS/SIGNIFICANCE: These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

Hepatitis E: Discovery, global impact, control and cure

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Khuroo, Mohammad S; Khuroo, Mehnaaz S; Khuroo, Naira S

2016-01-01

Hepatitis E was identified as an epidemic of non-A, non-B hepatitis from Kashmir, India in 1978. Hepatitis E virus (HEV), the etiological agent is the sole member of family Hepeviridae. The virus has marked heterogeneity and infects many animals like bats, camel, chicken, deer, boar, mongoose, pigs, rats, rabbit and cutthroat trout. Hepatitis E is a disease with a major global impact and has two distinct epidemiological patterns. Hepatitis E is an imperative health issue in developing nations...

Central nervous system immunoreactive somatostatin, substance P and met-enkephalin concentrations in experimental hepatic encephalopathy in the rat

Energy Technology Data Exchange (ETDEWEB)

Miller, J.L.; Millar, R.P.; Kirsch, R. (Cape Town Univ. (South Africa))

1982-06-12

Immunoreactive somatostatin, substance P and met-enkephalin concentrations were measured in various regions of the rat brain 65 hours after portacaval shunt and compared with concentrations in sham-operated animals. No significant difference was detected in any of the three peptides in the regions studied, suggesting that these peptides do not play a role in the pathogenesis of hepatic encephalopathy.

The influence of parenteral nitrogen feeding on free amino acid composition of blood serum and hepatic tissue of irradiated rats

International Nuclear Information System (INIS)

Mil'ko, V.I.; Kirichenko, A.V.; Chalaya, L.A.

1985-01-01

A considerable change in the free am ino acid composition of blood serum and hepatic tissued was noted on the 7th and 14th days following total-body X-irradiation of rats with a dose of 2.9 Gy. The total free amino acid content of blood serum increased and that of hepatic tissue decreased by 85% (on an average) as compared to the intact controls. Quantitative changes in the content of individual amino acids were analysed. Polyamine injected enterally for 7 days and parenterally for 3 days after irradiation a the elimination of the postirradiation changes in the amino acid balance

Hypolipidemic effect of dietary pea proteins: Impact on genes regulating hepatic lipid metabolism.

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Rigamonti, Elena; Parolini, Cinzia; Marchesi, Marta; Diani, Erika; Brambilla, Stefano; Sirtori, Cesare R; Chiesa, Giulia

2010-05-01

Controversial data on the lipid-lowering effect of dietary pea proteins have been provided and the mechanisms behind this effect are not completely understood. The aim of the study was to evaluate a possible hypolipidemic activity of a pea protein isolate and to determine whether pea proteins could affect the hepatic lipid metabolism through regulation of genes involved in cholesterol and fatty acid homeostasis. Rats were fed Nath's hypercholesterolemic diets for 28 days, the protein sources being casein or a pea protein isolate from Pisum sativum. After 14 and 28 days of dietary treatment, rats fed pea proteins had markedly lower plasma cholesterol and triglyceride levels than rats fed casein (pPea protein-fed rats displayed higher hepatic mRNA levels of LDL receptor versus those fed casein (ppea protein-fed rats than in rats fed casein (ppea proteins in rats. Moreover, pea proteins appear to affect cellular lipid homeostasis by upregulating genes involved in hepatic cholesterol uptake and by downregulating fatty acid synthesis genes.

The hepatic Raldh1 expression is elevated in Zucker fatty rats and its over-expression introduced the retinal-induced Srebp-1c expression in INS-1 cells.

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Yang Li

Full Text Available The roles of vitamin A (VA in the development of metabolic diseases remain unanswered. We have reported that retinoids synergized with insulin to induce the expression of sterol-regulatory element-binding protein 1c gene (Srebp-1c expression in primary rat hepatocytes. Additionally, the hepatic Srebp-1c expression is elevated in Zucker fatty (ZF rats, and reduced in those fed a VA deficient diet. VA is metabolized to retinoic acid (RA for regulating gene expression. We hypothesized that the expression of RA production enzymes contributes to the regulation of the hepatic Srebp-1c expression. Therefore, we analyzed their expression levels in Zucker lean (ZL and ZF rats. The mRNA levels of retinaldehyde dehydrogenase family 1 gene (Raldh1 were found to be higher in the isolated and cultured primary hepatocytes from ZF rats than that from ZL rats. The RALDH1 protein level was elevated in the liver of ZF rats. Retinol and retinal dose- and time-dependently induced the expression of RA responsive Cyp26a1 gene in hepatocytes and hepatoma cells. INS-1 cells were identified as an ideal tool to study the effects of RA production on the regulation of gene expression because only RA, but not retinal, induced Srebp-1c mRNA expression in them. Recombinant adenovirus containing rat Raldh1 cDNA was made and used to infect INS-1 cells. The over-expression of RALDH1 introduced the retinal-mediated induction of Srebp-1c expression in INS-1 cells. We conclude that the expression levels of the enzymes for RA production may contribute to the regulation of RA responsive genes, and determine the responses of the cells to retinoid treatments. The elevated hepatic expression of Raldh1 in ZF rats may cause the excessive RA production from retinol, and in turn, result in higher Srebp-1c expression. This excessive RA production may be one of the factors contributing to the elevated lipogenesis in the liver of ZF rats.

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.

Independent effects of sham laparotomy and anesthesia on hepatic microRNA expression in rats.

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Werner, Wiebke; Sallmon, Hannes; Leder, Annekatrin; Lippert, Steffen; Reutzel-Selke, Anja; Morgül, Mehmet Haluk; Jonas, Sven; Dame, Christof; Neuhaus, Peter; Iacomini, John; Tullius, Stefan G; Sauer, Igor M; Raschzok, Nathanael

2014-10-08

Studies on liver regeneration following partial hepatectomy (PH) have identified several microRNAs (miRNAs) that show a regulated expression pattern. These studies involve major surgery to access the liver, which is known to have intrinsic effects on hepatic gene expression and may also affect miRNA screening results. We performed two-third PH or sham laparotomy (SL) in Wistar rats to investigate the effect of both procedures on miRNA expression in liver tissue and corresponding plasma samples by microarray and qRT-PCR analyses. As control groups, non-treated rats and rats undergoing anesthesia only were used. We found that 49 out of 323 miRNAs (15%) were significantly deregulated after PH in liver tissue 12 to 48 hours postoperatively (>20% change), while 45 miRNAs (14%) were deregulated following SL. Out of these miRNAs, 10 miRNAs were similarly deregulated after PH and SL, while one miRNA showed opposite regulation. In plasma, miRNA upregulation was observed for miR-133a and miR-133b following PH and SL, whereas miR-100 and miR-466c were similarly downregulated following anesthesia and surgery. We show that miRNAs are indeed regulated by sham laparotomy and anesthesia in rats. These findings illustrate the critical need for finding appropriate control groups in experimental surgery.

Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats.

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Faria, Juliana A; Kinote, Andrezza; Ignacio-Souza, Letícia M; de Araújo, Thiago M; Razolli, Daniela S; Doneda, Diego L; Paschoal, Lívia B; Lellis-Santos, Camilo; Bertolini, Gisele L; Velloso, Lício A; Bordin, Silvana; Anhê, Gabriel F

2013-07-15

Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients.

Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors.

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Elaidy, Samah M; Hussain, Mona A; El-Kherbetawy, Mohamed K

2018-05-01

Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg -1 ·day -1 ) or NTZ (200 mg·kg -1 ·day -1 ) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.

Expression of Glutathione Peroxidase and Glutathione Reductase and Level of Free Radical Processes under Toxic Hepatitis in Rats

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Igor Y. Iskusnykh

2013-01-01

Full Text Available Correlation between intensity of free radical processes estimated by biochemiluminesce parameters, content of lipoperoxidation products, and changes of glutathione peroxidase (GP, EC 1.11.1.9 and glutathione reductase (GR, EC 1.6.4.2 activities at rats liver injury, after 12, 36, 70, 96, 110, and 125 hours & tetrachloromethane administration have been investigated. The histological examination of the liver sections of rats showed that prominent hepatocytes with marked vacuolisation and inflammatory cells which were arranged around the necrotic tissue are more at 96 h after exposure to CCl4. Moreover maximum increase in GR and GP activities, 2.1 and 2.5 times, respectively, was observed at 96 h after exposure to CCl4, what coincided with the maximum of free radical oxidation processes. Using a combination of reverse transcription and real-time polymerase chain reaction, expression of the glutathione peroxidase and glutathione reductase genes (Gpx1 and Gsr was analyzed by the determination of their respective mRNAs in the rat liver tissue under toxic hepatitis conditions. The analyses of Gpx1 and Gsr expression revealed that the transcript levels increased in 2.5- and 3.0-folds, respectively. Western blot analysis revealed that the amounts of hepatic Gpx1 and Gsr proteins increased considerably after CCl4 administration. It can be proposed that the overexpression of these enzymes could be a mechanism of enhancement of hepatocytes tolerance to oxidative stress.

Efek Hepatoprotektif Rosella (Hibiscus sabdariffa L. pada Tikus Model Hepatitis

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Ike Rostikawati Husen

2012-06-01

Full Text Available Hepatitis is initiated by pollutant which caused oxidative stress. Rosella (Hibiscus sabdariffa L. contain flavonoid, an antioxidant which has been used traditionally in treating liver disease. The study aims to define the hepatoprotective effects of fresh rosella calyx ethanol extract (FRCEE on hepatitis model rats with liver malondialdehyde (MDA and serum glutamic piruvic transaminase (SGPT level and hepatocyte morphology damage compared to vitamin E’s effects. The laboratory experimental study has been conducted on August 2009 at Department Pharmacology and Therapy Faculty of Medicine Padjadjaran University/Dr. Hasan Sadikin Hospital in 25 male Wistar rats, divided into 5 groups. Group 1 was negative control, group 2 was positive control (carbon tetrachloride/CCl4-hepatitis model rats, group 3 and 4 were hepatitis model rats that subsequently given 125 mg/kgBW of FRCEE (group 3 and 2.7 IU of vitamin E (group 4 for 8 days; group 5 was given FRCEE. Observations were done 48 hours after CCL4 induction. The results were analyzed by analysis of varian (ANOVA and Tukey. The result showed that FRCEE inhibited increasing of liver MDA and SGPT level significantly different compared to positive control (MDA p=0.00, SGPT p=0.041 but not significantly different to group 4 (MDA p=1.00, SGPT p=0.192. Histological features showed macrovesicular on group 3, microvesicular vacuole on group 2; whereas vitamin E inhibited morphological damage. In conclusion, FRCEE has hepatoprotective effect on hepatitis model rats as antioxidant, but not superior compared to vitamin E.

Ameliorating role of rutin on oxidative stress induced by iron overload in hepatic tissue of rats.

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Aziza, Samy Ali Hussein; Azab, Mohammed El-Said; El-Shall, Soheir Kamal

2014-08-01

Iron is an essential element that participates in several metabolic activities of cells; however, excess iron is a major cause of iron-induced oxidative stress and several human diseases. Natural flavonoids, as rutin, are well-known antioxidants and could be efficient protective agents. Therefore, the present study was undertaken to evaluate the protective influence of rutin supplementation to improve rat antioxidant systems against IOL-induced hepatic oxidative stress. Sixty male albino rats were randomly divided to three equal groups. The first group, the control, the second group, iron overload group, the third group was used as iron overload+rutin group. Rats received six doses of ferric hydroxide polymaltose (100 mg kg(-1) b.wt.) as one dose every two days, by intraperitoneal injections (IP) and administrated rutin (50 mg kg(-1) b.wt.) as one daily oral dose until the sacrificed day. Blood samples for serum separation and liver tissue specimens were collected three times, after three, four and five weeks from the onset of the experiment. Serum iron profiles total iron, Total Iron Binding Capacity (TIBC), Unsaturated Iron Binding Capacity (UIBC), transferrin (Tf) and Transferrin Saturation% (TS%)}, ferritin, albumin, total Protein, total cholesterol, triacylglycerols levels and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were determined. Moreover, total iron in the liver, L-malondialdehyde (L-MDA), glutathione (GSH), Nitric Oxide (NO) and Total Nucleic Acid (TNA) levels and glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activities were also determined. The obtained results revealed that, iron overload (IOL) resulted in significant increase in serum iron, TIBC, Tf, TS% and ferritin levels and AST and ALT activities and also increased liver iron, L-MDA and NO levels. Meanwhile, it decreased serum UIBC, total cholesterol, triacylglycerols, albumin, total protein and liver GSH, TNA levels and Gpx, CAT

Physiological activities of the combination of fish oil and α-lipoic acid affecting hepatic lipogenesis and parameters related to oxidative stress in rats.

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Ide, Takashi

2018-06-01

We studied the combined effect of fish oil and α-lipoic acid on hepatic lipogenesis and fatty acid oxidation and parameters of oxidative stress in rats fed lipogenic diets high in sucrose. A control diet contained a saturated fat (palm oil) that gives high rate of hepatic lipogenesis. Male Sprague-Dawley rats were fed diets supplemented with 0 or 2.5 g/kg α-lipoic acid and containing 0, 20, or 100 g/kg fish oil, for 21 days. α-Lipoic acid significantly reduced food intake during 0-8 days but not the later period of the experiment. Fish oil and α-lipoic acid decreased serum lipid concentrations and their combination further decreased the parameters in an additive fashion. The combination of fish oil and α-lipoic acid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Fish oil increased the parameters of hepatic fatty acid oxidation enzymes. α-Lipoic acid appeared to antagonize the stimulating effects of fish oil of fatty acid oxidation through reductions in the activity of some fatty acid oxidation enzymes. α-Lipoic acid attenuated fish oil-dependent increases in serum and liver malondialdehyde levels, and this compound also reduced the serum 8-hydroxy-2'-deoxyguanosine level. α-Lipoic acid affected various parameters related to the antioxidant system; fish oil also affected some of the parameters. The combination of fish oil and α-lipoic acid effectively reduced serum lipid levels through the additive down-regulation of hepatic lipogenesis. α-Lipoic acid was effective in attenuating fish oil-mediated oxidative stress.

Gut microbiota are linked to increased susceptibility to hepatic steatosis in low aerobic capacity rats fed an acute high fat diet

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Poor aerobic fitness is linked to nonalcoholic fatty liver disease and increased all-cause mortality. We previously found that low capacity running (LCR) rats fed acute high fat diet (HFD; 45% kcal from fat) for 3 days resulted in positive energy balance and increased hepatic steatosis compared with...

Sulfur amino acids metabolism in magnesium deficient rats

Energy Technology Data Exchange (ETDEWEB)

Tojo, H.; Kosokawa, Y.; Yamaguchi, K.

1984-01-01

Effect of magnesium (Mg) deficiency on sulfur amino acid metabolism was investigated in rats. Young male rats were fed on the diet containing either 2.26 (deficient rats) or 63.18 mg Mg/100g diet (control and low protein rats) for 2 weeks. A remarkable decrease of body weight gain, serum Mg contents and a slight decreases in the hematological parameters such as Hb, Ht and RBC was observed, while the hepatic Mg and Ca was not significantly changed. Erythema and cramps were observed 5 days after feeding on the Mg-depleted diet. The hepatic glutathione and cysteine contents increased in Mg-deficient rats. However, no significant change of cysteine dioxygenase (CDO) activity and taurine content in Mg-deficient rat liver was observed. These results suggest that Mg deficiency affects the utilization and biosynthesis of hepatic glutathione but not the cysteine catabolism.

A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P rats.

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Jonathon D Klein

Full Text Available Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day in inbred alcohol-preferring (iP10a rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.

A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P) rats.

Science.gov (United States)

Klein, Jonathon D; Sherrill, Jeremy B; Morello, Gabriella M; San Miguel, Phillip J; Ding, Zhenming; Liangpunsakul, Suthat; Liang, Tiebing; Muir, William M; Lumeng, Lawrence; Lossie, Amy C

2014-01-01

Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d) is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P) rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day) in inbred alcohol-preferring (iP10a) rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.

Red peppers with moderate and severe pungency prevent the memory deficit and hepatic insulin resistance in diabetic rats with Alzheimer's disease.

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Yang, Hye Jeong; Kwon, Dae Young; Kim, Min Jung; Kang, Suna; Moon, Na Rang; Daily, James W; Park, Sunmin

2015-01-01

Dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis, but red pepper extract improves glucose homeostasis. We therefore evaluated whether long-term oral consumption of different red pepper extracts improves cognitive dysfunction and glucose homeostasis in type 2 diabetic rats with β-amyloid-induced dementia. Male diabetic rats received hippocampal CA1 infusions of β-amyloid (25-35) (AD) or β-amyloid (35-25, non-plaque forming), at a rate of 3.6 nmol/day for 14 days (Non-AD). AD rats were divided into four dietary groups receiving either 1% lyophilized 70% ethanol extracts of either low, moderate and severe pungency red peppers (AD-LP, AD-MP, and AD-SP) or 1% dextrin (AD-CON) in Western diets (43% energy as fat). The ascending order of control memory deficit measured by passive avoidance test and water maze test. Furthermore, the accumulation of β-amyloid induced glucose intolerance, although serum insulin levels were elevated during the late phase of oral glucose tolerance test (OGTT). All of the red pepper extracts prevented the glucose intolerance in AD rats. Consistent with OGTT results, during euglycemic hyperinulinemic clamp glucose infusion rates were lower in AD-CON than Non-AD-CON with no difference in whole body glucose uptake. Hepatic glucose output at the hyperinsulinemic state was increased in AD-CON. β-amyloid accumulation exacerbated hepatic insulin resistance, but all red pepper extract treatments reversed the insulin resistance in AD rats. The extracts of moderate and severe red peppers were found to prevent the memory deficit and exacerbation of insulin resistance by blocking tau phosphorylation and β-amyloid accumulation in diabetic rats with experimentally induced Alzheimer's-like dementia. These results suggest that red pepper consumption might be an effective intervention for preventing age-related memory deficit.

Effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat

International Nuclear Information System (INIS)

Stout, D.L.; Becker, F.F.

1988-01-01

The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of [ 3 H]leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When 55 FeCl 3 and [2- 14 C]glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme

Activation of neuronal nitric oxide synthase in cerebellum of chronic hepatic encephalopathy rats is associated with up-regulation of NADPH-producing pathway.

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Singh, Santosh; Trigun, Surendra K

2010-09-01

Cerebellum-associated functions get affected during mild hepatic encephalopathy (MHE) in patients with chronic liver failure (CLF). Involvement of nitrosative and antioxidant factors in the pathogenesis of chronic hepatic encephalopathy is an evolving concept and needs to be defined in a true CLF animal model. This article describes profiles of NADPH-dependent neuronal nitric oxide synthase (nNOS) and those of glutathione peroxidase and glutathione reductase (GR) vis-a-vis regulation of NADPH-producing pathway in the cerebellum of CLF rats induced by administration of thioacetamide (100 mg kg⁻¹ b.w., i.p.) up to 10 days and confirming MHE on Morris water maze tests. Significant increases in the expression of nNOS protein and nitric oxide (NOx) level coincided with a similar increment in NADPH-diaphorase activity in the cerebellum of CLF rats. Glutathione peroxidase and GR utilize NADPH to regenerate reduced glutathione (GSH) in the cells. Both these enzymes and GSH level were found to be static and thus suggested efficient turnover of GSH in the cerebellum of MHE rats. Relative levels of glucose-6-phosphate dehydrogenase (G6PD) vs. phosphofructokinase 2 (PFK2) determine the rate of pentose phosphate pathway (PPP) responsible to synthesize NADPH. The cerebellum of CLF rats showed overactivation of G6PD with a significant decline in the expression of PFK2 and thus suggested activation of PPP in the cerebellum during MHE. It is concluded that concordant activations of PPP and nNOS in cerebellum of MHE rats could be associated with the implication of NOx in the pathogenesis of MHE.

Multigenerational epigenetic adaptation of the hepatic wound-healing response.

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Zeybel, Müjdat; Hardy, Timothy; Wong, Yi K; Mathers, John C; Fox, Christopher R; Gackowska, Agata; Oakley, Fiona; Burt, Alastair D; Wilson, Caroline L; Anstee, Quentin M; Barter, Matt J; Masson, Steven; Elsharkawy, Ahmed M; Mann, Derek A; Mann, Jelena

2012-09-01

We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.

Failure of carnitine in improving hepatic nitrogen content in alcoholic and non-alcoholic malnourished rats

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Luciana P. Rodrigues

2010-01-01

Full Text Available AIMS: To investigate the effect of carnitine supplementation on alcoholic malnourished rats' hepatic nitrogen content. METHODS: Malnourished rats, on 50% protein-calorie restriction with free access to water (malnutrition group and malnourished rats under the same conditions with free access to a 20% alcohol/water solution (alcohol group were studied. After the undernourishment period (4 weeks with or without alcohol, both groups were randomly divided into two subgroups, one of them nutritionally recovered for 28 days with free access to a normal diet and water (recovery groups and the other re-fed with free access to diet and water plus carnitine (0.1 g/g body weight/day by gavage (carnitine groups. No alcohol intake was allowed during the recovery period. RESULTS: The results showed: i no difference between the alcohol/no alcohol groups, with or without carnitine, regarding body weight gain, diet consumption, urinary nitrogen excretion, plasma free fatty acids, lysine, methionine, and glycine. ii Liver nitrogen content was highest in the carnitine recovery non-alcoholic group (from 1.7 to 3.3 g/100 g, P.05 was highest in the alcoholic animals. CONCLUSION: Carnitine supplementation did not induce better nutritional recovery.

Dynamic expression of desmin, α-SMA and TGF-β1 during hepatic fibrogenesis induced by selective bile duct ligation in young rats

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Gonçalves, J.O.; Tannuri, A.C.A.; Coelho, M.C.M.; Bendit, I.; Tannuri, U. [Laboratório de Pesquisa em Cirurgia Pediátrica (LIM-30), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2014-08-15

We previously described a selective bile duct ligation model to elucidate the process of hepatic fibrogenesis in children with biliary atresia or intrahepatic biliary stenosis. Using this model, we identified changes in the expression of alpha smooth muscle actin (α-SMA) both in the obstructed parenchyma and in the hepatic parenchyma adjacent to the obstruction. However, the expression profiles of desmin and TGF-β1, molecules known to be involved in hepatic fibrogenesis, were unchanged when analyzed by semiquantitative polymerase chain reaction (RT-PCR). Thus, the molecular mechanisms involved in the modulation of liver fibrosis in this experimental model are not fully understood. This study aimed to evaluate the molecular changes in an experimental model of selective bile duct ligation and to compare the gene expression changes observed in RT-PCR and in real-time quantitative PCR (qRT‐PCR). Twenty-eight Wistar rats of both sexes and weaning age (21-23 days old) were used. The rats were separated into groups that were assessed 7 or 60 days after selective biliary duct ligation. The expression of desmin, α-SMA and TGF-β1 was examined in tissue from hepatic parenchyma with biliary obstruction (BO) and in hepatic parenchyma without biliary obstruction (WBO), using RT-PCR and qRT‐PCR. The results obtained in this study using these two methods were significantly different. The BO parenchyma had a more severe fibrogenic reaction, with increased α-SMA and TGF-β1 expression after 7 days. The WBO parenchyma presented a later, fibrotic response, with increased desmin expression 7 days after surgery and increased α-SMA 60 days after surgery. The qRT‐PCR technique was more sensitive to expression changes than the semiquantitative method.

Dynamic expression of desmin, α-SMA and TGF-β1 during hepatic fibrogenesis induced by selective bile duct ligation in young rats

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Gonçalves, J.O.; Tannuri, A.C.A.; Coelho, M.C.M.; Bendit, I.; Tannuri, U.

2014-01-01

We previously described a selective bile duct ligation model to elucidate the process of hepatic fibrogenesis in children with biliary atresia or intrahepatic biliary stenosis. Using this model, we identified changes in the expression of alpha smooth muscle actin (α-SMA) both in the obstructed parenchyma and in the hepatic parenchyma adjacent to the obstruction. However, the expression profiles of desmin and TGF-β1, molecules known to be involved in hepatic fibrogenesis, were unchanged when analyzed by semiquantitative polymerase chain reaction (RT-PCR). Thus, the molecular mechanisms involved in the modulation of liver fibrosis in this experimental model are not fully understood. This study aimed to evaluate the molecular changes in an experimental model of selective bile duct ligation and to compare the gene expression changes observed in RT-PCR and in real-time quantitative PCR (qRT‐PCR). Twenty-eight Wistar rats of both sexes and weaning age (21-23 days old) were used. The rats were separated into groups that were assessed 7 or 60 days after selective biliary duct ligation. The expression of desmin, α-SMA and TGF-β1 was examined in tissue from hepatic parenchyma with biliary obstruction (BO) and in hepatic parenchyma without biliary obstruction (WBO), using RT-PCR and qRT‐PCR. The results obtained in this study using these two methods were significantly different. The BO parenchyma had a more severe fibrogenic reaction, with increased α-SMA and TGF-β1 expression after 7 days. The WBO parenchyma presented a later, fibrotic response, with increased desmin expression 7 days after surgery and increased α-SMA 60 days after surgery. The qRT‐PCR technique was more sensitive to expression changes than the semiquantitative method

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.

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048

NARCIS (Netherlands)

van Dijk, T. H.; van der Sluijs, F. H.; Wiegman, C. H.; Baller, J. F.; Gustafson, L. A.; Burger, H. J.; Herling, A. W.; Kuipers, F.; Meijer, A. J.; Reijngoud, D. J.

2001-01-01

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats - A pharmacological study with the chlorogenic acid derivative S4048

NARCIS (Netherlands)

van Dijk, TH; van der Sluijs, FH; Wiegman, CH; Baller, JFW; Gustafson, LA; Burger, HJ; Herling, AW; Kuipers, F; Meijer, AJ; Reijngoud, DJ

2001-01-01

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in

Protein source in a high-protein diet modulates reductions in insulin resistance and hepatic steatosis in fa/fa Zucker rats.

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Wojcik, Jennifer L; Devassy, Jessay G; Wu, Yinghong; Zahradka, Peter; Taylor, Carla G; Aukema, Harold M

2016-01-01

High-protein diets are being promoted to reduce insulin resistance and hepatic steatosis in metabolic syndrome. Therefore, the effect of protein source in high-protein diets on reducing insulin resistance and hepatic steatosis was examined. Fa/fa Zucker rats were provided normal-protein (15% of energy) casein, high-protein (35% of energy) casein, high-protein soy, or high-protein mixed diets with animal and plant proteins. The high-protein mixed diet reduced area under the curve for insulin during glucose tolerance testing, fasting serum insulin and free fatty acid concentrations, homeostatic model assessment index, insulin to glucose ratio, and pancreatic islet cell area. The high-protein mixed and the high-protein soy diets reduced hepatic lipid concentrations, liver to body weight ratio, and hepatic steatosis rating. These improvements were observed despite no differences in body weight, feed intake, or adiposity among high-protein diet groups. The high-protein casein diet had minimal benefits. A high-protein mixed diet was the most effective for modulating reductions in insulin resistance and hepatic steatosis independent of weight loss, indicating that the source of protein within a high-protein diet is critical for the management of these metabolic syndrome parameters. © 2015 The Obesity Society.

Tomato Juice Consumption Modifies the Urinary Peptide Profile in Sprague-Dawley Rats with Induced Hepatic Steatosis

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Gala Martín-Pozuelo

2016-10-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common liver disorder in Western countries, with a high prevalence, and has been shown to increase the risk of type 2 diabetes, cardiovascular disease (CVD, etc. Tomato products contain several natural antioxidants, including lycopene—which has displayed a preventive effect on the development of steatosis and CVD. Accordingly, the aim of the present work was to evaluate the effect of tomato juice consumption on the urinary peptide profile in rats with NAFLD induced by an atherogenic diet and to identify potential peptide biomarkers for diagnosis. Urine samples, collected weekly for four weeks, were analyzed by capillary electrophoresis (CE coupled to a mass spectrometer (MS. A partial least squares-discriminant analysis (PLS-DA was carried out to explore the association between differential peptides and treatments. Among the 888 peptides initially identified, a total of 55 were obtained as potential biomarkers. Rats with steatosis after tomato juice intake showed a profile intermediate between that of healthy rats and that of rats with induced hepatic steatosis. Accordingly, tomato products could be considered as a dietary strategy for the impairment of NAFLD, although further research should be carried out to develop a specific biomarkers panel for NAFLD.

Tomato Juice Consumption Modifies the Urinary Peptide Profile in Sprague-Dawley Rats with Induced Hepatic Steatosis.

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Martín-Pozuelo, Gala; González-Barrio, Rocío; Barberá, Gonzalo G; Albalat, Amaya; García-Alonso, Javier; Mullen, William; Mischak, Harald; Periago, María Jesús

2016-10-26

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western countries, with a high prevalence, and has been shown to increase the risk of type 2 diabetes, cardiovascular disease (CVD), etc. Tomato products contain several natural antioxidants, including lycopene-which has displayed a preventive effect on the development of steatosis and CVD. Accordingly, the aim of the present work was to evaluate the effect of tomato juice consumption on the urinary peptide profile in rats with NAFLD induced by an atherogenic diet and to identify potential peptide biomarkers for diagnosis. Urine samples, collected weekly for four weeks, were analyzed by capillary electrophoresis (CE) coupled to a mass spectrometer (MS). A partial least squares-discriminant analysis (PLS-DA) was carried out to explore the association between differential peptides and treatments. Among the 888 peptides initially identified, a total of 55 were obtained as potential biomarkers. Rats with steatosis after tomato juice intake showed a profile intermediate between that of healthy rats and that of rats with induced hepatic steatosis. Accordingly, tomato products could be considered as a dietary strategy for the impairment of NAFLD, although further research should be carried out to develop a specific biomarkers panel for NAFLD.

Restorative Effects of Caffeic Acid Phenethyl Ester in Radiation-Induced Oxidative Hepatic Disorders

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El-Fatih, N.M.; EI-Tawil, G.A.

2009-01-01

The potential role of antioxidant natural phenolic compounds in the prevention of oxidative tissue-damage associated with ionizing-radiation has accumulated over the past decades. The possible restorative effect of caffeic acid phenethyl ester (CAPE) in minimizing radiation-induced hepatic injury in male albino rats was investigated. CAPE was given to rats via intraperitoneal (ip.) injection at a dose of (10μmol/ kg b.wt.) for 21 successive days throughout exposure to gamma radiation and continued for 15 successive days post gamma-radiation exposure. Whole body gamma-irradiation was delivered as fractionated doses (3 weeks) 2 Gy increment every week up to total cumulative dose of G Gy. Rats were sacrificed at either I, or 15 days after last dose of radiation. Malondialdehyde (MDA) content was determined in plasma and hepatic tissues. In addition, the activities of xanthine oxidase (XO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) as well as the level of reduced glutathione (GSH) were determined to evaluate the changes of antioxidant-status in blood systems and hepatic tissues. Meantime, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were estimated in rat serum. Results showed that exposure to gamma-radiation significantly increased the MDA levels and the activities of XO, ALT, AST and ALP. Moreover, SOD, CAT and GSH-Px activities as well GSH contents showed significant consumption in irradiated rats. Treatment with CAPE showed a significant decrease in MDA level and caused significant increases in all enzymes measured in hepatic tissues and blood systems when compared with irradiated group. Conclusion: radiation-exposure leads to a reduction in antioxidant enzymatic activities and causes lipid peroxidation in hepatic tissues and blood. Under experimental condition, CAPE exhibits restorative effects on gamma-rays-induced hepatic-oxidative impairment in rats

Restorative Effects of Caffeic Acid Phenethyl Ester in Radiation-Induced Oxidative Hepatic Disorders

International Nuclear Information System (INIS)

El-Fatih, N.M.; EI-Tawil, G.A.

2008-01-01

The potential role of antioxidant natural phenolic compounds in the prevention of oxidative tissue-damage associated with ionizing-radiation has accumulated over the past decades. The possible restorative effect of caffeic acid phenethyl ester (CAPE) in minimizing radiation-induced hepatic injury in male albino rats was investigated. CAPE was given to rats via intraperitoneal (ip.) injection at a dose of (10μmol/ kg b.wt.) for 21 successive days throughout exposure to gamma radiation and continued for 15 successive days post gamma-radiation exposure. Whole body gamma-irradiation was delivered as fractionated doses (3 weeks) 2 Gy increment every week up to total cumulative dose of G Gy. Rats were sacrificed at either I, or 15 days after last dose of radiation. Malondialdehyde (MDA) content was determined in plasma and hepatic tissues. In addition, the activities of xanthine oxidase (XO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) as well as the level of reduced glutathione (GSH) were determined to evaluate the changes of antioxidant-status in blood systems and hepatic tissues. Meantime, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were estimated in rat serum. Results showed that exposure to gamma-radiation significantly increased the MDA levels and the activities of XO, ALT, AST and ALP. Moreover, SOD, CAT and GSH-Px activities as well GSH contents showed significant consumption in irradiated rats. Treatment with CAPE showed a significant decrease in MDA level and caused significant increases in all enzymes measured in hepatic tissues and blood systems when compared with irradiated group. Conclusion: radiation-exposure leads to a reduction in antioxidant enzymatic activities and causes lipid peroxidation in hepatic tissues and blood. Under experimental condition, CAPE exhibits restorative effects on gamma-rays-induced hepatic-oxidative impairment in rats

Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.

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Shaker, Mohamed E; Salem, Hatem A; Shiha, Gamal E; Ibrahim, Tarek M

2011-04-01

The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

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.

Time course of collagen peak in bile duct-ligated rats.

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Tarcin, Orhan; Basaranoglu, Metin; Tahan, Veysel; Tahan, Gülgün; Sücüllü, Ilker; Yilmaz, Nevin; Sood, Gagan; Snyder, Ned; Hilman, Gilbert; Celikel, Cigdem; Tözün, Nurdan

2011-04-28

One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4-wk bile duct-ligated model is suitable in animal fibrogenesis trials. Of the 53 male Wistar rats, 8 (Group 0) were used as a healthy control group. Bile duct ligation (BDL) had been performed in the rest. Bile duct-ligated rates were sacrificed 7 days later in group 1 (10 rats), 14 days later in group 2 (9 rats), 21 days later in group 3(9 rats) and 28 days later in group 4 (9 rats). Eight rats underwent sham-operation (Sham). Hepatic collagen measurements as well as serum levels of liver enzymes and function tests were all analysed. The peak level of collagen was observed biochemically and histomorphometricly at the end of third week (P fibrosis in bile duct-ligated rats is transient, i.e. reverses spontaneously after 3 weeks. This contrasts any situation in patients where hepatic fibrosis is progressive and irreversible as countless studies performed by many investigators in the same animal model.

The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats

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Celalettin Semih Kunak

2015-01-01

Full Text Available Ischemia-reperfusion (I/R damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. Objective. This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. Material and Methods. Experimental animals were divided into four groups as liver I/R control (LIRC, 50 mg/kg etoricoxib + liver I/R (ETO-50, 100 mg/kg etoricoxib + liver I/R (ETO-100, and healthy group (HG. ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. Results. Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting.

Effect of Chromatin-Remodeling Agents in Hepatic Differentiation of Rat Bone Marrow-Derived Mesenchymal Stem Cells In Vitro and In Vivo

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Danna Ye

2016-01-01

Full Text Available Epigenetic events, including covalent histone modifications and DNA methylation, play fundamental roles in the determination of lineage-specific gene expression and cell fates. The aim of this study was to determine whether the DNA methyltransferase inhibitor (DNMTi 5-aza-2′-deoxycytidine (5-aza-dC and the histone deacetylase inhibitor (HDACi trichostatin A (TSA promote the hepatic differentiation of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs and their therapeutic effect on liver damage. 1 μM TSA and 20 μM 5-aza-dC were added to standard hepatogenic medium especially at differentiation and maturation steps and their potential function on hepatic differentiation in vitro and in vivo was determined. Exposure of rBM-MSCs to 1 μM TSA at both the differentiation and maturation steps considerably improved hepatic differentiation. TSA enhanced the development of the hepatocyte shape, promoted the chronological expression of hepatocyte-specific markers, and improved hepatic functions. In contrast, treatment of rBM-MSCs with 20 μM 5-aza-dC alone or in combination with TSA was ineffective in improving hepatic differentiation in vitro. TSA and/or 5-aza-dC derived hepatocytes-like cells failed to improve the therapeutic potential in liver damage. We conclude that HDACis enhance hepatic differentiation in a time-dependent manner, while DNMTis do not induce the hepatic differentiation of rBM-MSCs in vitro. Their in vivo function needs further investigation.

Short and long-term impact of lipectomy on expression profile of hepatic anabolic genes in rats: a high fat and high cholesterol diet-induced obese model.

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Ling, Bey-Leei; Chiu, Chun-Tang; Lu, Hsiu-Chin; Lin, Jin-Jin; Kuo, Chiung-Yin; Chou, Fen-Pi

2014-01-01

To understand the molecular basis of the short and long-term effects of an immediate shortage of energy storage caused by lipectomy on expression profile of genes involved in lipid and carbohydrate metabolism in high fat and high cholesterol diet-induced obese rats. The hepatic mRNA levels of enzymes, regulator and transcription factors involved in glucose and lipid metabolism were analyzed by quantitative real time polymerase chain reaction (RT-qPCR) ten days and eight weeks after lipectomy in obese rats. Body and liver weights and serum biochemical parameters, adiponectin, leptin and insulin were determined. No significant difference was observed on the food intake between the lipectomized and sham-operated groups during the experimental period. Ten days after the operation, the lipectomized animals showed significant higher triacylglycerol, glucose and insulin levels, a lower adiponectin concentration than the sham-operated rats, along with significant higher hepatic mRNA levels of hepatocyte nuclear factor 4α (HNF4α) and the enzymes involved in lipogenesis, sterol biosynthesis and gluconeogenesis. The results of immunohistochemical (IHC) analysis also confirmed increased levels of lipogenic enzymes in the liver of lipectomized versus sham-operated animals. The lipectomized group had a significantly lower adiponectin/leptin ratio that was positively correlated to the level of LDL (r = 0.823, Pshort term enhancement of the expression of hepatic anabolic genes involved in lipid and carbohydrate metabolism was triggered that might eventually lead to the final extra weight gain. These metabolic changes could be the results of reduced circulating adiponectin that further influences the functions of insulin and hepatic HNF4α.

Regeneração do fígado de ratos após oclusão parcial da drenagem venosa hepática Hepatic regeneration after parcial oclusion of hepatic vein drainage in rats

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Luiz Roberto Farion de Aguiar

2009-06-01

the loss of liver functional tissue. This process has been studied through different methods. AIM: To evaluate the effect of the partial occlusion of the hepatic venous drainage on the regeneration of the remainder livers in rats submitted to partial hepatectomy. METHOD: Liver biopsies from 30 male Wistar rats were collected, and after they were submitted two-third hepatectomy. The animals were divided in three groups: a control group and two study groups, which were submitted to different degrees of the right hepatic vein stenosis. After 96 hours of the stimulation for regeneration all rats were submitted to another hepatic biopsy. The analysis of the fragments was performed by immunohistochemistry for the Ki-67 and von Willebrand factor markers. The reading of the samples was done using the SAMBA 4000 system. Collagen deposition was evaluated by the trichromic Masson's staining. RESULT: The cellular proliferation of the animals submitted to partial hepatectomy and stenosis of the right hepatic vein persists higher when compared to control group. The Label Index for Ki-67 was significantly higher post-hepatectomy in groups submitted to hepatic vein partial occlusion. The expression of von Willebrand factor was strongly decreased after the hepatectomy in all groups. There was little deposit of collagen in the hepatic tissue of animals with hepatic vein stenosis. CONCLUSION: Partial occlusion of the hepatic venous drainage in rats submitted to partial hepatectomy prolongs the time of hepatic cells proliferation when compared to the animals with vein of normal caliber. Consequently, there will be also a delay in the restoration of the extracellular matrix and in the formation of new sinusoidal vessels.

Profiling of hepatic gene expression in rats treated with fibric acid analogs

International Nuclear Information System (INIS)

Cornwell, Paul D.; Souza, Angus T. de; Ulrich, Roger G.

2004-01-01

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal β-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARα activation, although signaling through other receptors (e.g. PPARγ, RXR) or through non-receptor pathways cannot be excluded

Physiological covalent regulation of rat liver branched-chain alpha-ketoacid dehydrogenase

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Harris, R.A.; Powell, S.M.; Paxton, R.; Gillim, S.E.; Nagae, H.

1985-01-01

A radiochemical assay was developed for measuring branched-chain alpha-ketoacid dehydrogenase activity of Triton X-100 extracts of freeze-clamped rat liver. The proportion of active (dephosphorylated) enzyme was determined by measuring enzyme activities before and after activation of the complex with a broad-specificity phosphoprotein phosphatase. Hepatic branched-chain alpha-ketoacid dehydrogenase activity in normal male Wistar rats was 97% active but decreased to 33% active after 2 days on low-protein (8%) diet and to 13% active after 4 days on the same diet. Restricting protein intake of lean and obese female Zucker rats also caused inactivation of hepatic branched-chain alpha-ketoacid dehydrogenase complex. Essentially all of the enzyme was in the active state in rats maintained for 14 days on either 30 or 50% protein diets. This was also the case for rats maintained on a commercial chow diet (minimum 23% protein). However, maintaining rats on 20, 8, and 0% protein diets decreased the percentage of the active form of the enzyme to 58, 10, and 7% of the total, respectively. Fasting of chow-fed rats for 48 h had no effect on the activity state of hepatic branched-chain alpha-ketoacid dehydrogenase, i.e., 93% of the enzyme remained in the active state compared to 97% for chow-fed rats. However, hepatic enzyme of rats maintained on 8% protein diet was 10% active before starvation and 83% active after 2 days of starvation. Thus, dietary protein deficiency results in inactivation of hepatic branched-chain alpha-ketoacid dehydrogenase complex, presumably as a consequence of low hepatic levels of branched-chain alpha-ketoacids

High Fat Diet Exposure during Fetal Life Enhances Plasma and Hepatic Omega-6 Fatty Acid Profiles in Fetal Wistar Rats

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Marlon E. Cerf

2015-08-01

Full Text Available Pregnant rats were fed a high fat diet (HFD for the first (HF1, second (HF2, third (HF3 or all three weeks (HFG of gestation. Maintenance on a HFD during specific periods of gestation was hypothesized to alter fetal glycemia, insulinemia, induce insulin resistance; and alter fetal plasma and hepatic fatty acid (FA profiles. At day 20 of gestation, fetal plasma and hepatic FA profiles were determined by gas chromatography; body weight, fasting glycemia, insulinemia and the Homeostasis Model Assessment (HOMA-insulin resistance were also determined. HF3 fetuses were heaviest concomitant with elevated glycemia and insulin resistance (p < 0.05. HFG fetuses had elevated plasma linoleic (18:2 n-6 and arachidonic (20:4 n-6 acid proportions (p < 0.05. In the liver, HF3 fetuses displayed elevated linoleic, eicosatrienoic (20:3 n-6 and arachidonic acid proportions (p < 0.05. HFG fetuses had reduced hepatic docosatrienoic acid (22:5 n-3 proportions (p < 0.05. High fat maintenance during the final week of fetal life enhances hepatic omega-6 FA profiles in fetuses concomitant with hyperglycemia and insulin resistance thereby presenting a metabolically compromised phenotype.

Chemical and biological insights into uranium-induced apoptosis of rat hepatic cell line

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Liu, Fang; You, Yong [University of South China, College of Hunan Province, Key Laboratory of Tumor Cellular and Molecular Pathology, Hengyang (China); Du, Ke-Jie [University of South China, School of Chemistry and Chemical Engineering, Hengyang (China); Fang, Zhen [Anhui Normal University, College of Chemistry and Materials Science, Wuhu (China); Wen, Ge-Bo [University of South China, College of Hunan Province, Key Laboratory of Tumor Cellular and Molecular Pathology, Hengyang (China); University of South China, Laboratory of Protein Structure and Function, Hengyang (China); Lin, Ying-Wu [University of South China, School of Chemistry and Chemical Engineering, Hengyang (China); University of South China, Laboratory of Protein Structure and Function, Hengyang (China)

2015-05-15

Uranium release into the environment is a threat to human health, and the mechanisms of cytotoxicity caused by uranium are not well-understood. To improve our understanding in this respect, we herein evaluated the effects of uranium exposure on normal rat hepatic BRL cells. As revealed by scanning electron microscopy and transmission electron microscope analysis, uranyl nitrate was found to be transformed into uranyl phosphate particles in the medium and taken up by BRL cells in an endocytotic uptake manner, which presumably initiates apoptosis of the cell, although soluble uranyl ion may also be toxic. The apoptosis of BRL cells upon uranium exposure was also confirmed by both the acridine orange and ethidium bromide double staining assay and the Annexin V/propidium iodide double staining assay. Further studies revealed that uranium induced the loss of mitochondrial membrane potential in a dose-dependent manner. Moreover, the uranium-induced apoptosis was found to be associated with the activation of caspase-3, caspase-8 and caspase-9, indicating both a mitochondria-dependent signaling pathway and a death receptor pathway by a crosstalk. This study provides new chemical and biological insights into the mechanism of uranium toxicity toward hepatic cells, which will help seek approaches for biological remediation of uranium. (orig.)

A krill oil supplemented diet suppresses hepatic steatosis in high-fat fed rats.

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Ferramosca, Alessandra; Conte, Annalea; Burri, Lena; Berge, Kjetil; De Nuccio, Francesco; Giudetti, Anna Maria; Zara, Vincenzo

2012-01-01

Krill oil (KO) is a dietary source of n-3 polyunsaturated fatty acids, mainly represented by eicosapentaenoic acid and docosahexaenoic acid bound to phospholipids. The supplementation of a high-fat diet with 2.5% KO efficiently prevented triglyceride and cholesterol accumulation in liver of treated rats. This effect was accompanied by a parallel reduction of the plasma levels of triglycerides and glucose and by the prevention of a plasma insulin increase. The investigation of the molecular mechanisms of KO action in high-fat fed animals revealed a strong decrease in the activities of the mitochondrial citrate carrier and of the cytosolic acetyl-CoA carboxylase and fatty acid synthetase, which are both involved in hepatic de novo lipogenesis. In these animals a significant increase in the activity of carnitine palmitoyl-transferase I and in the levels of carnitine was also observed, suggesting a concomitant stimulation of hepatic fatty acid oxidation. The KO supplemented animals also retained an efficient mitochondrial oxidative phosphorylation, most probably as a consequence of a KO-induced arrest of the uncoupling effects of a high-fat diet. Lastly, the KO supplementation prevented an increase in body weight, as well as oxidative damage of lipids and proteins, which is often found in high-fat fed animals.

Age-associated alterations in hepatic β-adrenergic receptor/adenylate cyclase complex

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Graham, S.M.; Herring, P.A.; Arinze, I.J.

1987-01-01

The effect of age on catecholamine regulation of hepatic glycogenolysis and on hepatic adenylate cyclase was studied in male rats up to 24 mo of age. Epinephrine and norepinephrine stimulated glycogenolysis in isolated hepatocytes at all age groups studied. Isoproterenol, however, stimulated glycogenolysis only at 24 mo. In isolated liver membranes, usual activators of adenylate cyclase increased the activity of the enzyme considerably more in membranes from 24-mo-old rats than in membranes from either 3- or 22-mo-old rats. The Mn 2+ -dependent activity of the cyclase was increased by 2.9-fold in 3-mo-old animals and ∼ 5.7-fold in 24-mo-old rats, indicating a substantial age-dependent increase in the intrinsic activity of the catalytic unit. The density of the β-adrenergic receptor, as measured by the binding of [ 125 I]-iodocyanopindolol to plasma membranes, was 5-8 fmol/mg protein in rats aged 3-12 mo but increased to 19 fmol/mg protein in 24-mo-old rats. Computer-aided analysis of isoproterenol competition of the binding indicated a small age-dependent increase in the proportion of β-receptors in the high-affinity state. These observations suggest that β-receptor-mediated hepatic glycogenolysis in the aged rat is predicated upon increases in the density of β-receptors as well as increased intrinsic activity of the catalytic unit of adenylate cyclase

Effect of exogenous leptin on serum levels of lipids, glucose, renal and hepatic variables in both genders of obese and streptozotocin-induced diabetic rats

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Parichehr Hayatdavoudi

2015-11-01

Full Text Available Objective(s: Leptin exerts various effects on appetite and body weight. Disruption of the obesitygene is precedent to fatness. Insulin or glucose elevates leptin, but streptozotocin reduces it. However, controversial data exist for the effects of leptin on diabetes and leptin level in each gender. Leptin can damage the kidney function but little evidence exists for its hepatic effects. The aim of this study was to investigate the probable sex-dependent differences in blood sugar levels, lipid profile, and renal and hepatic biochemical factors in the obesity and streptozotocin-induced diabetic rats after leptin administration. Materials and Methods: Wistar rats of both sexes were randomly divided into two groups, namely obese and diabetic rats. Each group was further divided into male and female subgroups. Extra fat and carbohydrate was added to the diet to induce obesity. Furthermore, streptozotocin (55 mg/kg, IP was injected to induce diabetes. The treatment groups received leptin (0.1 mg/kg SC for 10 days, and then, blood samples were taken from the orbital sinus for laboratory evaluations. Results: Leptin resulted in a significant weight loss in both sexes (P

Peculiarities of the free radical processes in rat liver mitochondria under toxic hepatitis on the background of alimentary protein deficiency

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G. P. Kopylchuk

2016-04-01

Full Text Available The rate of superoxide anion radical, hydroxyl radical and hydrogen peroxide generation, the level of oxidative modification of mitochondrial proteins in the liver of rats with toxic hepatitis was investigated on the background of alimentary protein deficiency. We did not find significant increases of the intensity of free radical processes in liver mitochondria of rats maintained on the protein-deficient ration. The most significant intensification of free radical processes in liver mitochondria is observed under the conditions of toxic hepatitis, induced on the background of alimentary protein deprivation. Under these conditions the aggravation of all studied forms of reactive oxygen species generation was observed in liver mitochondria. The generation rates were increased as follows: O2 – by 1.7 times, Н2О2 – by 1.5 times, •ОН – practically double on the background of accumulation of oxidized mitochondria-derived proteins. The established changes in thiol groups’ redox status of respiratory chain proteins insoluble in 0.05 M sodium-phosphate buffer (pH 11.5, and changes of their carbonyl derivatives content may be considered as one of the regulatory factors of mitochondrial energy-generating function.

Protective mechanism of turmeric (Curcuma longa) on carbofuran-induced hematological and hepatic toxicities in a rat model.

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Hossen, Md Sakib; Tanvir, E M; Prince, Maruf Billah; Paul, Sudip; Saha, Moumoni; Ali, Md Yousuf; Gan, Siew Hua; Khalil, Md Ibrahim; Karim, Nurul

2017-12-01

Turmeric (Curcuma longa L. [Zingiberaceae]) is used in the treatment of a variety of conditions including pesticide-induced toxicity. The study reports the antioxidant properties and the protective effects of turmeric against carbofuran (CF)-induced toxicity in rats. The antioxidant potential was determined by using free radicals scavenging activity and ferric reducing antioxidant power values. Male Wistar rats were randomly divided into four groups, designated as control, turmeric (100 mg/kg/day), CF (1 mg/kg/day) and turmeric (100 mg/kg/day) + CF (1 mg/kg/day) treatments. All of the doses were administered orally for 28 consecutive days. The biological activity of the turmeric and CF was determined by using several standard biochemical methods. Turmeric contains high concentrations of polyphenols (8.97 ± 0.15 g GAEs), flavonoids (5.46 ± 0.29 g CEs), ascorbic acid (0.06 ± 0.00 mg AEs) and FRAP value (1972.66 ± 104.78 μM Fe 2+ ) per 100 g of sample. Oral administration of CF caused significant changes in some of the blood indices, such as, mean corpuscular volume, corpuscular hemoglobin, white blood cell, platelet distribution width and induced severe hepatic injuries associated with oxidative stress, as observed by the significantly higher lipid peroxidation (LPO) levels when compared to control, while the activities of cellular antioxidant enzymes (including superoxide dismutase and glutathione peroxidase) were significantly suppressed in the liver tissue. Turmeric supplementation could protect against CF-induced hematological perturbations and hepatic injuries in rats, plausibly by the up-regulation of antioxidant enzymes and inhibition of LPO to confer the protective effect.

Saponins, especially platycodin D, from Platycodon grandiflorum modulate hepatic lipogenesis in high-fat diet-fed rats and high glucose-exposed HepG2 cells

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Hwang, Yong Pil [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Department of Pharmaceutical Engineering, International University of Korea, Jinju (Korea, Republic of); Choi, Jae Ho; Kim, Hyung Gyun; Khanal, Tilak; Song, Gye Young [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Nam, Myoung Soo [College of Agriculture and Life Sciences, Chungnam National University, Daejeon (Korea, Republic of); Lee, Hyun-Sun [Molecular Cancer Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Chung, Young Chul; Lee, Young Chun [Division of Food Science, International University of Korea, Jinju (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

2013-03-01

AMP-activated protein kinase (AMPK) plays a central role in controlling hepatic lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and sterol regulatory element-binding protein-1c (SREBP-1c) pathway. Saponins, particularly platycodin D, from the roots of Platycodon grandiflorum (Changkil saponins, CKS) have a variety of pharmacological properties, including antioxidant and hepatoprotective properties. The aim of this study was to investigate the effects of CKS on hepatic lipogenesis and on the expression of genes involved in lipogenesis, and the mechanisms involved. CKS attenuated fat accumulation and the induction of the lipogenic genes encoding SREBP-1c and fatty acid synthase in the livers of HFD-fed rats and in steatotic HepG2 cells. Blood biochemical analyses and histopathological examinations showed that CKS prevented liver injury. CKS and platycodin D each increased the phosphorylation of AMPK and acetyl-CoA carboxylase in HFD-fed rats and HepG2 cells. The use of specific inhibitors showed that platycodin D activated AMPK via SIRT1/CaMKKβ in HepG2 cells. This study demonstrates that CKS or platycodin D alone can regulate hepatic lipogenesis via an AMPK-dependent signalling pathway. - Highlights: ► CKS attenuated fat accumulation in HFD-fed rats and in steatotic HepG2 cells. ► CKS and its major component, platycodin D, inhibited the levels of SREBP-1 and FAS. ► CKS and platycodin D increased the phosphorylation of AMPK and ACC. ► Platycodin D activated AMPK via SIRT1/CaMKKβ in HepG2 cells.

Short and long-term impact of lipectomy on expression profile of hepatic anabolic genes in rats: a high fat and high cholesterol diet-induced obese model.

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Bey-Leei Ling

Full Text Available OBJECTIVE: To understand the molecular basis of the short and long-term effects of an immediate shortage of energy storage caused by lipectomy on expression profile of genes involved in lipid and carbohydrate metabolism in high fat and high cholesterol diet-induced obese rats. METHODS: The hepatic mRNA levels of enzymes, regulator and transcription factors involved in glucose and lipid metabolism were analyzed by quantitative real time polymerase chain reaction (RT-qPCR ten days and eight weeks after lipectomy in obese rats. Body and liver weights and serum biochemical parameters, adiponectin, leptin and insulin were determined. RESULTS: No significant difference was observed on the food intake between the lipectomized and sham-operated groups during the experimental period. Ten days after the operation, the lipectomized animals showed significant higher triacylglycerol, glucose and insulin levels, a lower adiponectin concentration than the sham-operated rats, along with significant higher hepatic mRNA levels of hepatocyte nuclear factor 4α (HNF4α and the enzymes involved in lipogenesis, sterol biosynthesis and gluconeogenesis. The results of immunohistochemical (IHC analysis also confirmed increased levels of lipogenic enzymes in the liver of lipectomized versus sham-operated animals. The lipectomized group had a significantly lower adiponectin/leptin ratio that was positively correlated to the level of LDL (r = 0.823, P<0.05 and negatively to glucose and insulin (r = -0.821 and -0.892 respectively, P<0.05. Eight weeks after the operation, the lipectomized animals revealed significant higher body and liver weights, weight gain, liver to body weight ratio, hepatic triacylglycerol and serum insulin level. CONCLUSIONS: In response to lipectomy a short term enhancement of the expression of hepatic anabolic genes involved in lipid and carbohydrate metabolism was triggered that might eventually lead to the final extra weight gain. These

The effect of phenobarbital on the metabolism and excretion of thyroxine in rats

International Nuclear Information System (INIS)

McClain, R.M.; Levin, A.A.; Posch, R.; Downing, J.C.

1989-01-01

The effect of phenobarbital on thyroid function and the metabolism and biliary excretion of thyroxine in rats was determined. Phenobarbital, administered for 2 weeks at a dose of 100 mg/kg/day, resulted in an increase in hepatic and thyroid gland weights, decreased circulating levels of T4, T3 and rT3, and increased TSH levels in male and female rats. After 3 months of treatment liver and thyroid weights were still increased; however, hormone values were not as markedly affected indicating that the rats had partially compensated for the effect on thyroid function. In thyroidectomized rats the plasma clearance of thyroxine was increased with phenobarbital. In bile duct cannulated phenobarbital-treated male rats the hepatic uptake at 4 hr was markedly increased. Bile flow was increased and the 4-hr cumulative biliary excretion of administered radioactivity was increased by 42%. Most of the increase in the excretion (76%) was accounted for by an increase in the excretion of thyroxine-glucuronide in phenobarbital-treated rats. Hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats expressed as picomoles per milligram of protein was increased by 40%; enzyme activity per gram of liver was increased by about twofold which, coupled with increased hepatic weight, resulted in about a threefold increase in total hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats as compared to that of controls. Qualitatively similar effects on metabolism, excretion, and enzyme induction were noted in female rats; however, the magnitude of increase was less than that observed in male rats. It is concluded that the effect of phenobarbital on thyroid function in rats is primarily a result of its effects on the hepatic disposition of thyroid hormone

Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.

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Deguchi, Yoshihito; Yamada, Tomoya; Hirose, Yukihiro; Nagahori, Hirohisa; Kushida, Masahiko; Sumida, Kayo; Sukata, Tokuo; Tomigahara, Yoshitaka; Nishioka, Kazuhiko; Uwagawa, Satoshi; Kawamura, Satoshi; Okuno, Yasuyoshi

2009-03-01

Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.

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.

Time course of collagen peak in bile duct-ligated rats

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Snyder Ned

2011-04-01

Full Text Available Abstract Background One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4-wk bile duct-ligated model is suitable in animal fibrogenesis trials. Methods Of the 53 male Wistar rats, 8 (Group 0 were used as a healthy control group. Bile duct ligation (BDL had been performed in the rest. Bile duct-ligated rates were sacrificed 7 days later in group 1 (10 rats, 14 days later in group 2 (9 rats, 21 days later in group 3(9 rats and 28 days later in group 4 (9 rats. Eight rats underwent sham-operation (Sham. Hepatic collagen measurements as well as serum levels of liver enzymes and function tests were all analysed. Results The peak level of collagen was observed biochemically and histomorphometricly at the end of third week (P Conclusion We have shown that fibrosis in bile duct-ligated rats is transient, i.e. reverses spontaneously after 3 weeks. This contrasts any situation in patients where hepatic fibrosis is progressive and irreversible as countless studies performed by many investigators in the same animal model.

Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2

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Kang, HE; Bae, SK; Yoo, M; Lee, DC; Kim, YG; Lee, MG

2009-01-01

Background and purpose: Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with α-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2. Experimental approach: Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg·kg−1) and/or tamsulosin (1 mg·kg−1). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (Ki) and [I]/Ki ratio of udenafil. Key results: The total area under the plasma concentration–time curve from time zero to time infinity (AUC)s (or AUC0–4h) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs. Conclusions and implications: The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia. PMID:19254278

Evaluation of the synergistic effect of Allium sativum, Eugenia jambolana, Momordica charantia, Ocimum sanctum and Psidium guajav on hepatic and intestinal drug metabolizing enzymes in rats

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Devendra Kumar

2016-12-01

Full Text Available Aims/Background: Present study investigated the synergistic effect of polyherbal formulations (PHF of Allium sativum L Eugenia jambolana Lam., Momordica charantia L., Ocimum sanctum Linn and Psidium guajava L. in the inhibition/induction of hepatic and intestinal CYPs and Phase-II conjugated drug metabolizing enzymes. Consumption of these herbal remedy has been extensively documented for diabetes treatment in Auyureda. Methodology: PHF of these five herbs was prepared and different doses were orally administered to Sprague Dawley rats of different groups except control group. Expression of mRNA and activity of drug metabolizing enzymes were examined by RT-PCR and HPLC in isolated liver and intestine microsomes in PHF pretreated rats. Results: Activities of hepatic and intestinal Phase-II enzyme levels increased along with mRNA levels except CYP3A mRNA level. PHF administration increases the activity of hepatic and intestinal UDPGT and GST in response to dose and time; however, activity of hepatic SULT increased at higher doses. Conclusions: CYPs and Phase-II conjugated enzymes levels can be modulated in dose and time dependent manner. Observations suggest that poly herbal formulation might be a possible cause of herb-drug interaction, due to changes in pharmacokinetic of crucial CYPs and Phase-II substrate drug. [J Complement Med Res 2016; 5(4.000: 372-382

Hepatic cholesterol metabolism following a chronic ingestion of cesium-137 starting at fetal stage in rats

International Nuclear Information System (INIS)

Racine, R.; Grandcolas, L.; Blanchardon, E.; Gourmelon, P.; Souidi, M.; Veyssiere, G.

2010-01-01

The Chernobyl accident released many radionuclides in the environment. Some are still contaminating the ground and thus the people through dietary intake. The long-term sanitary consequences of this disaster are still unclear and several biological systems remain to be investigated. Cholesterol metabolism is of particular interest, with regard to the link established between atherosclerosis and exposure to high-dose ionizing radiations. This study assesses the effect of cesium-137 on cholesterol metabolism in rats, after a chronic exposure since fetal life. To achieve this, rat dams were contaminated with cesium-137-supplemented water from two weeks before mating until the weaning of the pups. Thereafter, the weaned rats were given direct access to the contaminated drinking water until the age of 9 months. After the sacrifice, cholesterol metabolism was investigated in the liver at gene expression and protein level. The cholesterolemia was preserved, as well as the cholesterol concentration in the liver. At molecular level, the gene expressions of ACAT 2 (a cholesterol storage enzyme), of Apolipoprotein A-I and of RXR (a nuclear receptor involved in cholesterol metabolism) were significantly decreased. In addition, the enzymatic activity of CYP27A1, which catabolizes cholesterol, was increased. The results indicate that the rats seem to adapt to the cesium-137 contamination and display modifications of hepatic cholesterol metabolism only at molecular level and within physiological range. (author)

Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats.

Science.gov (United States)

Biazi, Giuliana R; Frasson, Isabele G; Miksza, Daniele R; de Morais, Hely; de Fatima Silva, Flaviane; Bertolini, Gisele L; de Souza, Helenir M

2018-05-15

The response to glucagon and adrenaline in cancer cachexia is poorly known. The aim of this study was to investigate the response to glucagon, adrenergic agonists (α and β) and cyclic adenosine monophosphate (cAMP) on glycogenolysis, gluconeogenesis, and glycolysis in liver perfusion of Walker-256 tumor-bearing rats with advanced cachexia. Liver ATP content was also investigated. Rats without tumor (healthy) were used as controls. Agonists α (phenylephrine) and β (isoproterenol) adrenergic, instead of adrenaline, and cAMP, the second messenger of glucagon and isoproterenol, were used in an attempt to identify mechanisms involved in the responses. Glucagon (1 nM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in the liver of healthy and tumor-bearing rats, but their effects were lower in tumor-bearing rats. Isoproterenol (20 µM) stimulated glycogenolysis, gluconeogenesis, and glycolysis in healthy rats and had virtually no effect in tumor-bearing rats. cAMP (9 µM) also stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in healthy rats but had practically no effect in tumor-bearing rats. Phenylephrine (2 µM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis and these effects were also lower in tumor-bearing rats than in healthy. Liver ATP content was lower in tumor-bearing rats. In conclusion, tumor-bearing rats with advanced cachexia showed a decreased hepatic response to glucagon, adrenergic agonists (α and β), and cAMP in glycogenolysis, gluconeogenesis, and glycolysis, which may be due to a reduced rate of regulatory enzyme phosphorylation caused by the low ATP levels in the liver. © 2018 Wiley Periodicals, Inc.

Effects of sh-reagents on rat hepatic aldehyde dehydrogenase activity

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Konoplitskaya, K.L.; Kuz' mina, G.I.; Grigor' yeva, M.V.; Poznyakova, T.N.

The liver serves as the primary organ for the oxidation of ingested ethanol via a pathway involving alcohol- and aldehyde dehydrogenase. In view of the problem of alcoholism, three enzymes are of particular interest in understanding the biochemical mechanism that may be involved in alcohol addiction and in the formulation of therapeutic approaches. While alcohol dehydrogenase has been studied in considerable detail, current attention is centered on aldehyde dehydrogenase. A comparative analysis of the effects of a series of SH-active reagents - tetraethylthiuram disulfide (TETD), 5,5-dithiobisnitrobenzoic acid (DTNB), p-chloromercurybenzoate (PCMB), and N-ethylmaleimide (NEM) - were tested for their effects on the activity of aldehyde dehydrogenase of the hepatic mitochondrial (isozymes I and II) and microsomal (isozyme II) fractions of outbred albino rats. DTNB was found to be inhibited by 100 and 50% mitochondrial isozymes I and II, respectively, and by 20%, the microsomal enzyme under the conditions employed. DTNB and NEM inhibited by 30 and 50% isozymes I and II of the mitochondria, but had no effect on the microsomal isozyme. 24 references, 3 figures.

Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

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El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

2016-01-01

The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

The protective effect of Murraya koenigii leaves against carbon tetra chloride-induced hepatic damage in rats

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Brahma Naidu Parimi

2014-04-01

Full Text Available Objective: To evaluate the efficacy of methanolic extract of Murraya koenigii (MMK leaves in attenuating the hepatic damage inflicted by carbon tetrachloride (CCl4, a potent oxidative stress inducer and a model hepatotoxicant. Methods: Rats were divided into six groups of five each: normal control group, CCl4 group, CCl 4+silymarin group, CCl4+MMK group (200 mg/kg body weight, CCl4+MMK group (300 mg/kg body weight and CCl4+MMK group (500 mg/kg body weight. Rats were intraperitoneally injected with 20% CCl4 in corn oil (1 mL/kg body weight and MMK was orally administered for 3 weeks. Levels of hepatic markers such as alanine transaminase, aspartate transaminase, alkaline phosphatase and total bilirubin were measured. Activities of superoxide dismutase, catalase and glutathione peroxidase were assayed and malondialdehyde content was measured. For histopathological examination, liver microtome sections were prepared and observed under light microscope. Results: Oral administration of MMK had significantly reduced the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin content in a dosedependent manner, which were elevated by CCl 4. However, CCl 4-induced rise in lipid peroxidation and drop in superoxide dismutase, catalase and glutathione peroxidase activities were reversed by MMK administration. Further, the hepatoprotective activity of MMK was supported by histopathological examination of liver microtome sections. Conclusions: Our biochemical and histological studies demonstrate the potential antioxidant and hepatoprotective activity of MMK and our results scientifically validate the often use of MMK leaves in food preparation and in Ayurvedic medicine in India and neighboring countries.

Influence of Expression Plasmid of Connective Tissue Growth Factor and Tissue Inhibitor of Metalloproteinase-1 shRNA on Hepatic Precancerous Fibrosis in Rats.

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Zhang, Qun; Shu, Fu-Li; Jiang, Yu-Feng; Huang, Xin-En

2015-01-01

In this study, influence caused by expression plasmids of connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) short hairpin RNA (shRNA) on mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII in hepatic tissue with hepatic fibrosis, a precancerous condition, in rats is analyzed. To screen and construct shRNA expression plasimid which effectively interferes RNA targets of CTGF and TIMP-1 in rats. 50 cleaning Wistar male rats are allocated randomly at 5 different groups after precancerous fibrosis models and then injection of shRNA expression plasimids. Plasmid psiRNA-GFP-Com (CTGF and TIMP-1 included), psiRNA-GFP-CTGF, psiRNA-GFP-TIMP-1 and psiRNA- DUO-GFPzeo of blank plasmid are injected at group A, B, C and D, respectively, and as model control group that none plasimid is injected at group E. In 2 weeks after last injection, to hepatic tissue at different groups, protein expression of CTGF, TIMP-1, procol-α1and PC III is tested by immunohistochemical method and,mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII is measured by real-time PCR. One-way ANOVA is used to comparison between-groups. Compared with model group, there is no obvious difference of mRNA expression among CTGF,TIMP-1,procol-α1,PC III and of protein expression among CTGF, TIMP-1, procol-α1, PC III in hepatic tissue at group injected with blank plasmid. Expression quantity of mRNA of CTGF, TIMP-1, procol-α1 and PCIII at group A, B and C decreases, protein expression of CTGF, TIMP-1, procol-α1, PC III in hepatic tissue is lower, where the inhibition of combination RNA interference group (group A) on procol-α1 mRNA transcription and procol-α1 protein expression is superior to that of single interference group (group B and C) (P<0.01 or P<0.05). RNA interference on CTGF and/or TIMP-1 is obviously a inhibiting factor for mRNA and protein expression of CTGF, TIMP-1, procol-α1 and PCIII. Combination RNA interference on genes of CTGF and TIMP-1 is superior

The influence of γ-radiation on biosynthesis of nuclear matrix proteins of hepatic cells of pregnant rats

International Nuclear Information System (INIS)

Mirkhamidova, P.; Shamsutdinova, G.T.; Mirakhmedov, A.K.; Filatova, L.S.; Bul'dyaeva, T.V.; Zbarskij, I.B.

1992-01-01

A study was made of incorporation of 35 S-methionine into nuclear matrix proteins of hepatic cells of pregnant rats and their embryos subjected to single γ-irradiation ( 60 Co, 1 and 2 Gy, 0.0233 Gy/s) on days 3, 13 and 17 of pregrnancy and embryogenesis. On day 21 of pregnancy and embryogenesis a decrease in the rate of incorporation of 35 S-methionine into nuclear matrix proteins was shown to be a function of radiation dose and time of pregnancy and embryogenesis on the moment of exposure

Profiling of hepatic gene expression in rats treated with fibric acid analogs

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Cornwell, Paul D.; Souza, Angus T. de; Ulrich, Roger G

2004-05-18

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal {beta}-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPAR{alpha} activation, although signaling through other receptors (e.g. PPAR{gamma}, RXR) or through non-receptor pathways cannot be excluded.

Hepatic regeneration after sublethal partial liver irradiation in cirrhotic rats

International Nuclear Information System (INIS)

Gu Ke; Lai Songtao; Ma Ningyi; Zhao Jiandong; Ren Zhigang; Wang Jian; Liu Jin; Jiang Guoliang

2011-01-01

Our previous animal study had demonstrated that partial liver irradiation (IR) could stimulate regeneration in the protected liver, which supported the measurements adopted in radiotherapy planning for hepatocellular carcinoma. The purpose of this present study is to investigate whether cirrhotic liver repopulation could be triggered by partial liver IR. The cirrhosis was induced by thioacetamide (TAA) in rats. After cirrhosis establishment, TAA was withdrawn. In Experiment 1, only right-half liver was irradiated with single doses of 5 Gy, 10 Gy and 15 Gy, respectively. In Experiment 2, right-half liver was irradiated to 15 Gy, and the left-half to 2.5 Gy, 5 Gy and 7.5 Gy, respectively. The regeneration endpoints, including liver index (LI); mitotic index (MI); liver proliferation index (LPI); proliferating cell nuclear antigen-labeling index (PCNA-LI); serum hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α and interleukin (IL)-6, were evaluated on 0 day, 30-day, 60-day, 90-day, 120-day and 150-day after IR. Serum and in situ TGF-β1 were also measured. In both experimental groups, the IR injuries were sublethal, inducing no more than 9% animal deaths. Upon TAA withdrawal, hepatic regeneration decelerated in the controls. In Experiment 1 except for LI, all other regeneration parameters were significantly higher than those in controls for both right-half and left-half livers. In Experiment 2 all regeneration parameters were also higher compared with those in controls for both half livers. Serum HGF and VEGF were increased compared with that of controls. Both unirradiated and low dose-irradiated cirrhotic liver were able to regenerate triggered by sublethal partial liver IR and higher doses and IR to both halves liver triggered a more enhanced regeneration. (author)

Superiority of dietary safflower oil over olive oil in lowering serum cholesterol and increasing hepatic mRnas for the LDL receptor and cholesterol 7alpha-hydroxylase in exogenously hypercholesterolemic (exHC) rats.

Science.gov (United States)

Sato, M; Yoshida, S; Nagao, K; Imaizumi, K

2000-06-01

The exogenously hypercholesterolemic (ExHC) rat is a strain segregated from SD rats with a high response to dietary cholesterol. To understand the underlying mechanism(s) for this hypercholesterolemia, the interactive effects of dietary fatty acid and the susceptibility of rats to dietary cholesterol on the serum cholesterol concentration and hepatic mRNA abundance of the low-density lipoprotein (LDL) receptor, cholesterol 7alpha-hydroxylase (7alpha-hydroxylase) and 3-hydroxyl-3methylglutaryl (HMG) CoA reductase were examined. Both strains were fed on a diet supplemented with 10% each of olive, safflower or coconut oil with or without the addition of 1% cholesterol for one week. The ExHC rats fed on olive, safflower and coconut oil in combination with cholesterol respectively resulted in a 3.5-, 2.0- and 2.1-fold higher serum cholesterol concentration than that in the animals fed on the corresponding dietary fats without any supplementation of cholesterol (p safflower oil-containing diet supplemented with cholesterol resulted in a higher mRNA abundance of the LDL receptor and 7alpha-hydroxylase than in the corresponding fat-fed rats without cholesterol (p<0.05). There was no dietary cholesterol-dependent change of mRNA abundance in either strain fed on olive or coconut oil, except for a decreased abundance of HMG CoA reductase mRNA in the olive oil-fed ExHC rats and coconut oil-fed Sprague-Dawley (SD) rats (p<0.05). These results indicate that the hepatic mRNA abundance of the LDL receptor and of 7alpha-hydroxylase depended on the dietary combination of cholesterol and a fatty acid and suggest that a linoleic acid-rich diet may alleviate exogenous hypercholesterolemia by activating the process involved in the hepatic uptake and biliary excretion of serum cholesterol.

Jiao Tai Wan Attenuates Hepatic Lipid Accumulation in Type 2 Diabetes Mellitus

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Zhaoyi Huang

2013-01-01

Full Text Available Jiao Tai Wan (JTW, a Chinese herbal formula containing Rhizoma Coptidis and Cortex Cinnamomi, has been used for diabetic treatment for many years. The aim of this study was to determine the main components in JTW and to investigate the effects of JTW on hepatic lipid accumulation in diabetic rats and humans. JTW extract was prepared and the main components were assayed by HPLC. An animal model of diabetes mellitus was established and JTW was administered intragastrically. In the clinical study, diabetic patients with poor glycemic control were treated with JTW. Blood glucose and lipid parameters, liver histology, hepatic triglyceride content and lipogenic gene expression were examined. Our data demonstrated that JTW significantly improved hyperglycemia, hyperlipidemia and hepatic lipid accumulation in diabetic rats. This was accompanied by the down-regulation of acetyl coenzyme A carboxylase (ACC and fatty acid synthase (FAS protein expressions, and the up-regulation of AMP-activated protein kinase (AMPK and phosphorylated-ACC (pACC protein expressions in the liver tissues. Diabetic patients also exhibited decreases in their hepatic triglyceride content. The results suggest that JTW attenuates hepatic lipid accumulation in diabetic rats and humans. These beneficial effects are possibly associated with the inhibition of lipogenic gene expression in the liver.

Autoprotection in acetaminophen intoxication in rats

DEFF Research Database (Denmark)

Dalhoff, K; Laursen, H; Bangert, K

2001-01-01

and liver tissue were collected before and 12, 24, 36, and 48 hr after the toxic dose and were analysed for hepatic glutathione and cysteine contents, hepatic glutathione-S-transferase and blood alanine aminotransferase activity, as well as acetaminophen concentration in plasma. Steady-state mRNA levels......Autoprotection by acetaminophen, i.e. increased resistance to toxic effects caused by pretreatment, is a well-known phenomenon. The purpose of the present work was to identify mechanisms for increased acetaminophen tolerance induced by pretreatment of rats. One group of female Wistar rats...... (pretreated rats) received acetaminophen orally in increasing doses (1 to 4.3 g/kg) twice a week for 3 weeks, one group (naïve rats) received the vehicle. At time zero pretreated rats received a toxic dose of 7.5 g/kg (100% lethal in naïve rats), and naïve rats received a toxic dose of 4.3 g/kg. Blood...

Ameliorative Effect of Gallic Acid on Cyclophosphamide-Induced Oxidative Injury and Hepatic Dysfunction in Rats

Science.gov (United States)

Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Ola, Olaniyi Solomon; Adeyemo, Oluwatobi Adewumi

2015-01-01

Cyclophosphamide (CP), a bifunctional alkylating agent used in chemotherapy has been reported to induce organ toxicity mediated by generation of reactive oxygen species and oxidative stress. Gallic acid (GA), a phenolic substance, is a natural antioxidant with proven free radical scavenging activity and offers protection against oxidative damage. This research study was designed to investigate the ameliorative effect of GA against CP-induced toxicity in rats. Twenty-five male Wistar rats (180–200 g) were randomized into five treatment groups: (A) control, (B) CP, 2 mg/kg body weight (b.w.), (C) pre-treatment with GA (20 mg/kg b.w.) for seven days followed by CP (2 mg/kg b.w.) for seven days, (D) co-treatment with GA (20 mg/kg b.w) and CP (2 mg/kg b.w.) for seven days, and (E) GA (20 mg/kg b.w.) for seven days. CP induced marked renal and hepatic damages as plasma levels of urea, creatinine, bilirubin and activities of AST, ALT, ALP and GGT were significantly elevated (p acid. PMID:29083393

Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease.

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Liu, Yanjun; Shi, Di; Tian, Yingying; Liu, Yuntao; Zhan, Qiping; Xu, Jie; Wang, Jingfeng; Xue, Changhu

2017-02-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7α-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor α (PPARα) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARα and AMPK.

Histopathological, oxidative damage, biochemical, and genotoxicity alterations in hepatic rats exposed to deltamethrin: modulatory effects of garlic (Allium sativum).

Science.gov (United States)

Ncir, Marwa; Ben Salah, Ghada; Kamoun, Hassen; Makni Ayadi, Fatma; Khabir, Abdelmajid; El Feki, Abdelfattah; Saoudi, Mongi

2016-06-01

Deltamethrin is a pesticide widely used as a synthetic pyrethroid. The aim of this study was undertaken to investigate the effects of deltamethrin to induce oxidative stress and changes in biochemical parameters, hepatotoxicity and genotoxicity in female rats following a short-term (30 days) oral exposure and attenuation of these effects by Allium sativum extract. Indeed, Allium sativum is known to be a good antioxidant food resource which helps destroy free radical particles. Our results showed that deltamethrin treatment caused an increase in liver enzyme activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH); and hepatic lipid peroxidation (LPO) level. However, it induced a decrease in activities of hepatic catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (p Allium sativum extract normalized significantly (p Allium sativum diminished the adverse effects induced by this synthetic pyrethroid insecticide.

Hepatoprotective Activity of Methanolic Extract of Bauhinia purpurea Leaves against Paracetamol-Induced Hepatic Damage in Rats

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F. Yahya

2013-01-01

Full Text Available In an attempt to further establish the pharmacological properties of Bauhinia purpurea (Fabaceae, hepatoprotective potential of methanol extract of B. purpurea leaves (MEBP was investigated using the paracetamol- (PCM- induced liver toxicity in rats. Five groups of rats (n=6 were used and administered orally once daily with 10% DMSO (negative control, 200 mg/kg silymarin (positive control, or MEBP (50, 250, and 500 mg/kg for 7 days, followed by the hepatotoxicity induction using paracetamol (PCM. The blood samples and livers were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH radical scavenging assay with the total phenolic content (TPC also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control, whereas maintenance of the normal hepatic structural was observed in group pretreated with silymarin and MEBP. Hepatotoxic rats pretreated with silymarin or MEBP exhibited significant decrease (P<0.05 in ALT and AST enzyme level. Moreover, the extract also exhibited antioxidant activity and contained high TPC. In conclusion, MEBP exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and high phenolic content and thus warrants further investigation.

Effect of sulfonylureas on hepatic fatty acid oxidation

International Nuclear Information System (INIS)

Patel, T.B.

1986-01-01

In isolated rat livers perfused with oleic acid (0.1 mM), infusion of tolbutamide or glyburide decreased the rate of ketogenesis in a dose-dependent manner. The inhibition of fatty acid oxidation was maximal at 2.0 mM and 10 μM concentrations of tolbutamide and glyburide, respectively. Neither tolbutamide nor glyburide inhibited ketogenesis in livers perfused with octanoate. The inhibition of hepatic ketogenesis by sulfonylureas was independent of perfusate oleic acid concentration. Additionally, in rat livers perfused with oleic acid in the presence of L-(-)-carnitine (10 mM), submaximal concentrations of tolbutamide and glyburide did not inhibit hepatic ketogenesis. Finally, glyburide infusion into livers perfused with [U- 1 $C]oleic acid (0.1 mM) increased the rate of 14 C label incorporation into hepatic triglycerides by 2.5-fold. These data suggest that both tolbutamide and glyburide inhibit long-chain fatty acid oxidation by inhibition the key regulatory enzyme, carnitine palmitoyltransferase I, most probably by competing with L-(-)-carnitine

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

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Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 China (China); Chonan, Ritsu [Koei Kogyo Co., Ltd., Tokyo, 101-0063 Japan (Japan); Yamahara, Johji [Pharmafood Institute, Kyoto, 602-8136 Japan (Japan); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 China (China); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000 Australia (Australia)

2014-10-15

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

International Nuclear Information System (INIS)

Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

2014-01-01

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

Changes in the pharmacokinetics of glibenclamide in rats with streptozotocin-induced diabetes mellitus

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Yuqing Li

2012-04-01

Full Text Available The aim of this study was to investigate the pharmacokinetics of glibenclamide (Gli administrated orally and intravenously to normal and diabetic rats. The AUC(0–720 min of orally administered Gli in diabetic rats (321.24 mg min/L was greater than that (57.752 mg min/L in normal rats. CL (0.019 L/min/kg was significantly slower than that (0.092 L/min/kg of normal rats. The AUC(0–480min of intravenous Gli in diabetic rats (1528.280 mg min/L also was significantly greater than that (509.523 mg min/L in normal rats, and CL was decreased approximately 3-fold. No significant difference in intestinal absorption of Gli was observed between normal and diabetic rats as determined by in situ single-pass intestinal perfusion. The clearance of Diclofenac (a substrate of CYP2C9 was determined to evaluate changes in hepatic drug-metabolizing enzyme activity in rats. The CL in diabetic rats was significantly lower (42.43% decrease than that in normal rats. Hepatic protein expression of CYP2C9 was measured using Western blot analysis; compared with normal rats, the hepatic protein expression of CYP2A9 was decreased in diabetic rats. Therefore, the slower clearance of Gli in diabetic rats can be attributed primarily to the lower expression of hepatic CYP2C9.

Freshwater Clam Extract Ameliorates Triglyceride and Cholesterol Metabolism through the Expression of Genes Involved in Hepatic Lipogenesis and Cholesterol Degradation in Rats

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Thomas Laurent

2013-01-01

Full Text Available The freshwater clam (Corbicula spp. is a popular edible bivalve and has been used as a folk remedy for liver disease in Asia. As a Chinese traditional medicine, it is said that freshwater clam ameliorates alcoholic intoxication and cholestasis. In this study, to estimate the practical benefit of freshwater clam extract (FCE, we compared the effects of FCE and soy protein isolate (SPI on triglyceride and cholesterol metabolism in rats. FCE and SPI lowered serum cholesterol, and FCE tended to reduce serum triglycerides. FCE enhanced fecal sterol excretion and hepatic mRNA levels of CYP7A1 and ABCG5 more substantially than SPI; however, both diets reduced hepatic cholesterol. Both of the diets similarly suppressed liver lipids improved Δ9-desaturated fatty acid profile, and FCE was associated with a reduction in FAS and SCD1 mRNA levels. Hepatic transcriptome analysis revealed that inhibition of lipogenesis-related gene expression may contribute to downregulation of hepatic triglycerides by FCE. FCE would have better potential benefits for preventing metabolic disorders, through greater improvement of metabolism of triglycerides and cholesterol, likely through a mechanism similar to SPI.

Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450

International Nuclear Information System (INIS)

Marinello, A.J.; Bansal, S.K.; Paul, B.; Koser, P.L.; Love, J.; Struck, R.F.; Gurtoo, H.L.

1984-01-01

The hepatic cytochrome P-450-mediated metabolism and metabolic activation of [chloroethyl-3H]cyclophosphamide [( chloroethyl-3H]CP) and [4-14C]cyclophosphamide [( 4-14C]CP) were investigated in vitro in the reconstituted system containing cytochrome P-450 isolated from phenobarbital-treated rats. In addition, hepatic microsomal binding and the hepatic microsome-mediated metabolism of [14C]acrolein, a metabolite of [4-14C]CP, were also investigated. The metabolism of [chloroethyl-3H]CP and [4-14C]CP to polar metabolites was found to depend on the presence of NADPH and showed concentration dependence with respect to cytochrome P-450 and NADPH:cytochrome P-450 reductase. Km and Vmax values were essentially similar. The patterns of inhibition by microsomal mixed-function oxidase inhibitors, anti-cytochrome P-450 antibody, and heat denaturation of the cytochrome P-450 were essentially similar, with subtle differences between [4-14C]CP and [chloroethyl-3H]CP metabolism. The in vitro metabolic activation of CP in the reconstituted system demonstrated predominant binding of [chloroethyl-3H]CP to nucleic acids and almost exclusive binding of [4-14C]CP to proteins. Gel electrophoresis-fluorography of the proteins in the reconstituted system treated with [4-14C]CP demonstrated localization of the 14C label in the cytochrome P-450 region. To examine this association further, hepatic microsomes were modified with [14C]acrolein in the presence and the absence of NADPH. The results confirmed covalent association between [14C]acrolein and cytochrome P-450 in the microsomes and also demonstrated further metabolism of [14C]acrolein, apparently to an epoxide, which is capable of binding covalently to proteins. The results of these investigations not only confirm the significance of primary metabolism but also emphasize the potential role of the secondary metabolism of cyclophosphamide in some of its toxic manifestations

Hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat and guinea pig

International Nuclear Information System (INIS)

Wroblewski, V.J.; Olson, J.R.

1985-01-01

Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the rat having an LD 50 about 25-fold greater than the guinea pig. The metabolism of TCDD was examined by incubating hepatocytes isolated from these animals with purified [ 14 C]TCDD (2.2 microM) for 8 hr. Over the 8-hr incubation, cytochrome P-450 content and ethoxyresorufin O-deethylase and benzphetamine N-demethylase activities were well maintained, indicating the functional viability of the hepatocytes. Quantitative differences were observed in the rate of [ 14 C]TCDD metabolism, with hepatocytes from control rats metabolizing TCDD at a rate 2.8-fold greater than hepatocytes from control guinea pigs. The role of the hepatic cytochrome P-450-448-dependent monooxygenase system in the metabolism of TCDD was examined through the use of hepatocytes isolated from animals pretreated with either TCDD or phenobarbital. The rate of [ 14 C]TCDD metabolite formation in hepatocytes from TCDD pretreated guinea pigs (0.26 +/- 0.14 pmol mg cell protein-1 hr-1) was unchanged from the control rate, while the rate in hepatocytes from TCDD pretreated rats was 3.2-fold greater than control and nine times greater than in hepatocytes from TCDD-pretreated guinea pigs. On the other hand, phenobarbital pretreatment produced little change in the rate of [ 14 C]TCDD metabolism in rat hepatocytes. These results suggest that TCDD may be metabolized by a TCDD inducible form of cytochrome P-448 which is expressed in the rat but not in the guinea pig

Hepatic iron overload is associated with hepatocyte apoptosis during Clonorchis sinensis infection.

Science.gov (United States)

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.

Intermittent fasting reduces body fat but exacerbates hepatic insulin resistance in young rats regardless of high protein and fat diets.

Science.gov (United States)

Park, Sunmin; Yoo, Kyung Min; Hyun, Joo Suk; Kang, Suna

2017-02-01

Intermittent fasting (IMF) is a relatively new dietary approach to weight management, although the efficacy and adverse effects have not been full elucidated and the optimal diets for IMF are unknown. We tested the hypothesis that a one-meal-per-day intermittent fasting with high fat (HF) or protein (HP) diets can modify energy, lipid, and glucose metabolism in normal young male Sprague-Dawley rats with diet-induced obesity or overweight. Male rats aged 5 weeks received either HF (40% fat) or HP (26% protein) diets ad libitum (AL) or for 3 h at the beginning of the dark cycle (IMF) for 5 weeks. Epidydimal fat pads and fat deposits in the leg and abdomen were lower with HP and IMF. Energy expenditure at the beginning of the dark cycle, especially from fat oxidation, was higher with IMF than AL, possibly due to greater activity levels. Brown fat content was higher with IMF. Serum ghrelin levels were higher in HP-IMF than other groups, and accordingly, cumulative food intake was also higher in HP-IMF than HF-IMF. HF-IMF exhibited higher area under the curve (AUC) of serum glucose at the first part (0-40 min) during oral glucose tolerance test, whereas AUC of serum insulin levels in both parts were higher in IMF and HF. During intraperitoneal insulin tolerance test, serum glucose levels were higher with IMF than AL. Consistently, hepatic insulin signaling (GLUT2, pAkt) was attenuated and PEPCK expression was higher with IMF and HF than other groups, and HOMA-IR revealed significantly impaired attenuated insulin sensitivity in the IMF groups. However, surprisingly, hepatic and skeletal muscle glycogen storage was higher in IMF groups than AL. The higher glycogen storage in the IMF groups was associated with the lower expression of glycogen phosphorylase than the AL groups. In conclusion, IMF especially with HF increased insulin resistance, possibly by attenuating hepatic insulin signaling, and lowered glycogen phosphorylase expression despite decreased fat mass in young

Effects of ionizing radiation on the activity of the major hepatic enzymes implicated in bile acid biosynthesis in the rat

International Nuclear Information System (INIS)

Souidi, M.; Scanff, P.; Grison, St.; Gourmelon, P.; Aigueperse, J.

2007-01-01

In the days following high-dose radiation exposure, damage to small intestinal mucosa is aggravated by changes in the bile acid pool reaching the gut. Intestinal bile acid malabsorption, as described classically, may be associated with altered hepatic bile acid biosynthesis, which was the objective of this work. The activity of the main rate-limiting enzymes implicated in the bile acid biosynthesis were evaluated in the days following an 8-Gy γ Co 60 total body irradiation of rats, with concomitant determination of biliary bile acid profiles and intestinal bile acid content. Modifications of biliary bile acid profiles, observed as early as the first post-irradiation day, were most marked at the third and fourth day, and resulted in an increased hydrophobicity index. In parallel, the intestinal bile acids' content was enhanced and hepatic enzymatic activities leading to bile acids were changed. A marked increase of sterol 12-hydroxylase and decrease of oxy-sterol 7-hydroxylase activity was observed at day 3, whereas both cholesterol 7-hydroxylase and oxy-sterol 7-hydroxylase activities were decreased at day 4 after irradiation. These results show, for the first time, radiation-induced modifications of hepatic enzymatic activities implicated in bile acid biosynthesis and suggest that they are mainly a consequence of radiation-altered intestinal absorption, which induces a physiological response of the entero-hepatic bile acid recirculation. (authors)

Downregulation of hepatic and intestinal ATP-binding-cassette transporters abcg5 and abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

NARCIS (Netherlands)

Bloks, VW; Bakker-van Waarde, WW; Verkade, HJ; Kema, IP; Havinga, R; Wolters, H; Schaap, FG; Sauer, PJJ; Vink, E; Groen, AK; Kuipers, F

ABSTRACT: P234 Downregulation of Hepatic and Intestinal ATP-Binding-Cassette Transporters Abcg5 and Abcg8 Expression Associated with Altered Sterol Fluxes in Rats with Streptozotocin-Induced Diabetes Vincent W. Bloks, Willie W. Bakker-van Waarde, Henkjan J. Verkade, Ido P. Kema, Rick Havinga, Henk

The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury

DEFF Research Database (Denmark)

Møller, Linda Maria Sevelsted; Fialla, Annette Dam; Schierwagen, Robert

2016-01-01

and immunohistochemistry. Hemodynamic effects of KCa3.1 inhibition were investigated in bile duct-ligated and carbon tetrachloride intoxicated rats. In vitro experiments were performed in rat hepatic stellate cells and hepatocytes. KCa3.1 expression was increased in rodent and human liver fibrosis and was predominantly...... observed in the hepatocytes. Inhibition of KCa3.1 aggravated liver fibrosis during carbon tetrachloride challenge but did not change hemodynamic parameters in portal hypertensive rats. In vitro, KCa3.1 inhibition leads to increased hepatocyte apoptosis and DNA damage, whereas proliferation of hepatic...

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.

Science.gov (United States)

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.

Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis.

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Xuan Xia

2011-02-01

Full Text Available Berberine (BBR is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French. It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK and Glucose-6-phosphatase (G6Pase, were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1, sterol regulatory element-binding protein 1c (SREBP1 and carbohydrate responsive element-binding protein (ChREBP were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

Sulforaphane-rich broccoli sprout extract improves hepatic abnormalities in male subjects

Science.gov (United States)

Kikuchi, Masahiro; Ushida, Yusuke; Shiozawa, Hirokazu; Umeda, Rumiko; Tsuruya, Kota; Aoki, Yudai; Suganuma, Hiroyuki; Nishizaki, Yasuhiro

2015-01-01

AIM: To evaluate effects of dietary supplementation of sulforaphane (SF)-rich broccoli sprout (BS) extract on hepatic abnormalities in Japanese male participants. METHODS: In a randomized, placebo-controlled, double blind trial, male participants with fatty liver received either BS capsules containing glucoraphanin [GR; a precursor of SF (n = 24)] or placebo (n = 28) for 2 mo. Liver function markers, serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively) and γ-glutamyl transpeptidase (γ-GTP) and an oxidative stress marker, urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), were measured and compared in participants before and after the trial period. In an animal model, chronic liver failure was induced in Sprague-Dawley rats by successive intraperitoneal injection with N-nitrosodimethylamine (NDMA) for 4 wk. Concomitantly, rats received AIN-76 diets supplemented with or without BS extract. Thereafter, rats were sacrificed, and their sera and livers were collected to measure serum liver function markers and hepatic levels of thiobarbituric acid reactive substances (TBARS) levels and hepatic glutathione S-transferase (GST) activity, a prototypical phase 2 antioxidant enzyme. RESULTS: Dietary supplementation with BS extract containing SF precursor GR for 2 mo significantly decreased serum levels of liver function markers, ALT [median (interquartile range), before: 54.0 (34.5-79.0) vs after supplementation: 48.5 (33.3-65.3) IU/L, P NDMA-induced chronic liver failure in rats, which was attributable to the suppression of the increase in TBARS through induction of hepatic phase 2 antioxidant enzymes including hepatic GST (86.6 ± 95.2 vs 107.8 ± 7.7 IU/g, P < 0.01). CONCLUSION: Dietary supplementation with BS extract containing the SF precursor GR is likely to be highly effective in improving liver function through reduction of oxidative stress. PMID:26604653

Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content.

Science.gov (United States)

Neschen, Susanne; Moore, Irene; Regittnig, Werner; Yu, Chun Li; Wang, Yanlin; Pypaert, Marc; Petersen, Kitt Falk; Shulman, Gerald I

2002-02-01

To examine the mechanism by which fish oil protects against fat-induced insulin resistance, we studied the effects of control, fish oil, and safflower oil diets on peroxisomal content, fatty acyl-CoA, diacylglycerol, and ceramide content in rat liver and muscle. We found that, in contrast to control and safflower oil-fed rats, fish oil feeding induced a 150% increase in the abundance of peroxisomal acyl-CoA oxidase and 3-ketoacyl-CoA thiolase in liver but lacked similar effects in muscle. This was paralleled by an almost twofold increase in hepatic peroxisome content (both P < 0.002 vs. control and safflower). These changes in the fish oil-fed rats were associated with a more than twofold lower hepatic triglyceride/diacylglycerol, as well as intramuscular triglyceride/fatty acyl-CoA, content. In conclusion, these data strongly support the hypothesis that n-3 fatty acids protect against fat-induced insulin resistance by serving as peroxisome proliferator-activated receptor-alpha ligands and thereby induce hepatic, but not intramuscular, peroxisome proliferation. In turn, an increased hepatic beta-oxidative capacity results in lower hepatic triglyceride/diacylglycerol and intramyocellular triglyceride/fatty acyl-CoA content.

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Science.gov (United States)

Shin, Andrew C; Fasshauer, Martin; Filatova, Nika; Grundell, Linus A; Zielinski, Elizabeth; Zhou, Jian-Ying; Scherer, Thomas; Lindtner, Claudia; White, Phillip J; Lapworth, Amanda L; Ilkayeva, Olga; Knippschild, Uwe; Wolf, Anna M; Scheja, Ludger; Grove, Kevin L; Smith, Richard D; Qian, Wei-Jun; Lynch, Christopher J; Newgard, Christopher B; Buettner, Christoph

2014-11-04

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

Improvement effect of green tea on hepatic dysfunction, lipid ...

African Journals Online (AJOL)

We have evaluated the antioxidant effect of green tea on cadmium-induced hepatic dysfunction and stress oxidant in rats. Adult male Wistar rats were administered cadmium by injection with 20 μmoles/Kg bw/3 days for six months. Results revealed a significant (p < 0.05) liver dysfunction, lipid peroxidation and a decline in ...

Hepatic Antioxidant, Oxidative Stress And Histopathological ...

African Journals Online (AJOL)

Hepatic Antioxidant, Oxidative Stress And Histopathological Changes Induced By Nicotine In A Gender Based Study In Adult Rats. ... Antioxidant status was assessed in liver by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione-S-transferase (GST) and ...

Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity

International Nuclear Information System (INIS)

Boutros, Paul C.; Yao, Cindy Q.; Watson, John D.; Wu, Alexander H.; Moffat, Ivy D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo

2011-01-01

The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD 50 of > 9600 μg/kg for H/W rats is higher than for any other wild-type mammal known. We previously showed that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 μg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome.

Cilostazol attenuates cholestatic liver injury and its complications in common bile duct ligated rats.

Science.gov (United States)

Abdel Kawy, Hala S

2015-04-05

Cilostazol is a phosphodiesterase III inhibitor increases adenosine 3', 5'-cyclic monophosphate (cyclic AMP) level which inhibits hepatic stellate cell activation. Its pharmacological effects include vasodilation, inhibition of vascular smooth muscle cell growth, inhibition of platelet activation and aggregation. The aim of the current study was to determine the effects of early administration of low dose cilostazol on cholestatic liver injury induced by common bile duct ligation (CBDL) in rat. Male Wistar rats (180-200g) were divided into three groups: Group A; simple laparotomy group (sham). Group B; CBDL, Group C; CBDL rats treated with cilostazol (9mg/kg daily for 21 days). Six rats from each group were killed by the end of weeks one and three after surgery, livers and serum were collected for biochemical and histopathological studies. Aspartate aminotransferase, alanine aminotransferase, gama glutamyl transferase, alkaline phosphatase and total bilirubin serum levels decreased in the cilostazol treated rats, when compared with CBDL rats. The hepatic levels of tumor necrosis factor-alpha, transforming growth factor-beta, and platelet derived growth factor-B were significantly lower in cilostazol treated rats than that in CBDL rats. Cilostazol decreased vascular endothelial growth factor level and hemoglobin content in the livers. Cilostazol significantly lowered portal pressure, inhibited ductular proliferation, portal inflammation, hepatic fibrosis and decreased hepatic hydroxyproline contents. Administration of cilostazol in CBDL rats improved hepatic functions, decreased ductular proliferation, ameliorated portal inflammation, lowered portal hypertension and reduced fibrosis. These effects of cilostazol may be useful in the attenuation of liver injury in cholestasis. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of some anti-diabetic plants on the hepatic marker enzymes ...

African Journals Online (AJOL)

This study was embarked upon in order to evaluate the effects of the chloroform extracts of the leaves of Psidium guajava, Anacardium occidentale and Eucalyptus globulus and fruits of Xylopia aethiopica on hepatic marker enzymes of diabetic rats. The degree of hepatic damage caused by diabetes mellitus and the effects ...

Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

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Daniela Rodrigues

2012-12-01

Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy

International Nuclear Information System (INIS)

Basile, A.S.; Pannell, L.; Jaouni, T.; Gammal, S.H.; Fales, H.M.; Jones, E.A.; Skolnick, P.

1990-01-01

Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4- to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans

Investigation of hepatic fibrosis with synchrotron X-ray diffraction enhanced imaging

International Nuclear Information System (INIS)

Li Hui; Beijing Univ., Health Science Center, Beijing; Wang Xueyan; Zhao Tao; Hu Chunhong; Lu Weiyuan; Luo Shuqian; Wang Tailing; Wang Baoen; Zhao Xinyan; Zhu Peiping; Huang Wanxia; Yuan Qingxi; Wang Junyue

2008-01-01

In this paper, imaging investigation of hepatic fibrosis in rats induced by human albumin with hard X-ray diffraction enhanced imaging (DEI) is reported. The experiments were performed at 4W1A beamline of Beijing Synchrotron Radiation Facility (BSRF). The results show that great differences can be observed in DEI images between the normal and diseased rats in different stages of liver fibrosis. The difference can also be revealed by the profile curve and texture measurements on regions of interest. The results show that DEI may be a potential way for diagnosis of hepatic fibrosis. (authors)

Eleusine indica L. possesses antioxidant activity and precludes carbon tetrachloride (CCl₄)-mediated oxidative hepatic damage in rats.

Science.gov (United States)

Iqbal, Mohammad; Gnanaraj, Charles

2012-07-01

The purpose of this study was to evaluate the ability of aqueous extract of Eleusine indica to protect against carbon tetrachloride (CCl₄)-induced hepatic injury in rats. The antioxidant activity of E. indica was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay. The total phenolic content of E. indica was also determined. Biochemical parameters [e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), glutathione (GSH), catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase and quinone reductase] were used to evaluate hepatic damage in animals pretreated with E. indica and intoxicated with CCl₄. CCl₄-mediated hepatic damage was also evaluated by histopathologically. E. indica extract was able to reduce the stable DPPH level in a dose-dependent manner. The half maximal inhibitory concentration (IC₅₀) value was 2350 μg/ml. Total phenolic content was found to be 14.9 ± 0.002 mg/g total phenolic expressed as gallic acid equivalent per gram of extract. Groups pretreated with E. indica showed significantly increased activity of antioxidant enzymes compared to the CCl₄-intoxicated group (p indica pretreatment (p indica-pretreated groups as compared to the CCl₄-intoxicated group. The protective effect of E. indica was further evident through decreased histopathological alterations in the liver. The results of our study indicate that the hepatoprotective effects of E. indica might be ascribable to its antioxidant and free radical scavenging property.

Hepatic fat accumulation and regulation of FAT/CD36: an effect of hepatic irradiation

Science.gov (United States)

Martius, Gesa; Alwahsh, Salamah Mohammad; Rave-Fränk, Margret; Hess, Clemens Friedrich; Christiansen, Hans; Ramadori, Giuliano; Malik, Ihtzaz Ahmed

2014-01-01

Irradiation is known to induce inflammation and affect fat metabolic pathways. The current study investigates hepatic fat accumulation and fatty acid transportation in a rat model of single dose liver irradiation (25-Gy). Rat livers were selectively irradiated in-vivo (25-Gy), sham-irradiated rats served as controls. Hepatic lipids were studied by colorimetric assays in liver and serum. Intracellular lipids, protein and mRNA were studied by Nile red staining, immunohistology, Western Blot analysis and RT-PCR in liver, respectively. Changes in FAT/CD36 expression were studied in-vitro in a human monocyte cell line U937 after irradiation in presence or absence of infliximab (IFX). Nile Red staining of liver cryosections showed a quick (12-48 h) increase in fat droplets. Accordingly, hepatic triglycerides (TG) and free fatty acids (FFA) were elevated. An early increase (3-6 h) in the serum level of HDL-C, TG and cholesterol was measured after single dose irradiation followed by a decrease thereafter. Furthermore, expression of the fat transporter protein FAT/CD36 was increased, immunohistochemistry revealed basolateral and cytoplasmic expression in hepatocytes. Moreover, apolipoprotein-B100, -C3 and enzymes (acetyl-CoA carboxylase, lipoprotein-lipase, carnitine-palmitoyltransferase, malonyl-CoA-decarboxylase) involved in fat metabolism were induced at 12-24 h. Early activation of the NFkβ pathway (IκBα) by TNF-α was seen, followed by a significant elevation of serum markers for liver damage (AST and GLDH). TNF-α blockage by anti-TNF-α in cell culture (U937) prevented the increase of FAT/CD36 caused by irradiation. Selective liver irradiation is a model for rapid induction of steatosis hepatis and fat accumulation could be triggered by irradiation-induced inflammatory mediators (e.g. TNF-α). PMID:25197426

Protective Effect of Brazilian Propolis against Liver Damage with Cholestasis in Rats Treated with α-Naphthylisothiocyanate

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Tadashi Nakamura

2013-01-01

Full Text Available We examined the protective effect of Brazilian propolis against liver damage with cholestasis in rats treated with α-naphthylisothiocyanate (ANIT in comparison with that of vitamin E (VE. Rats orally received Brazilian propolis ethanol extract (BPEE (25, 50, or 100 mg/kg, VE (250 mg/kg or vehicle at 12 h after intraperitoneal injection of ANIT (75 mg/kg and were killed 24 h after the injection. Vehicle-treated rats showed liver cell damage and cholestasis, judging from the levels of serum marker enzymes and components. The vehicle group had increased serum total cholesterol, triglyceride, phospholipid, and lipid peroxide levels, increased hepatic lipid peroxide, reduced glutathione, and ascorbic acid levels and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. BPEE (50 mg/kg administered to ANIT-treated rats prevented liver cell damage and cholestasis and attenuated these serum and hepatic biochemical changes except hepatic ascorbic acid, although administered BPEE (25 or 100 mg/kg was less effective. VE administered to ANIT-treated rats prevented liver cell damage, but not cholestasis, and attenuated increased serum lipid peroxide level, increased hepatic lipid peroxide level and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. These results indicate that BPEE protects against ANIT-induced liver damage with cholestasis in rats more effectively than VE.

Activated rat hepatic stellate cells influence Th1/Th2 profile in vitro.

Science.gov (United States)

Xing, Zhi-Zhi; Huang, Liu-Ye; Wu, Cheng-Rong; You, Hong; Ma, Hong; Jia, Ji-Dong

2015-06-21

To investigate the effects of activated rat hepatic stellate cells (HSCs) on rat Th1/Th2 profile in vitro. Growth and survival of activated HSCs and CD4(+) T lymphocytes cultured alone or together was assessed after 24 or 48 h. CD4(+) T lymphocytes were then cultured with or without activated HSCs for 24 or 48 h and the proportion of Th1 [interferon (IFN)-γ(+)] and Th2 [interleukin (IL)-4(+)] cells was assessed by flow cytometry. Th1 and Th2 cell apoptosis was assessed after 24 h of co-culture using a caspase-3 staining procedure. Differentiation rates of Th1 and Th2 cells from CD4(+) T lymphocytes that were positive for CD25 but did not express IFN-γ or IL-4 were also assessed after 48 h of co-culture with activated HSCs. Galectin-9 expression in HSCs was determined by immunofluorescence and Western blotting. ELISA was performed to assess galectin-9 secretion from activated HSCs. Co-culture of CD4(+) T lymphocytes with activated rat HSCs for 48 h significantly reduced the proportion of Th1 cells compared to culture-alone conditions (-1.73% ± 0.71%; P Th1/Th2 ratio was significantly decreased (-0.44 ± 0.13; P Th1 cells was decreased (-65.71 ± 9.67; P Th1 (12.27% ± 0.99%; P Th1 cell apoptosis rate was significantly higher than in Th2 cells (P Th1 and Th2 cells; however, the increase in the proportion of Th2 cells was significantly higher than that of Th1 cells (1.85% ± 0.48%; P Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis.

Immunology taught by rats

OpenAIRE

Klenerman, P; Barnes, EJ

2017-01-01

Immunology may be best taught by viruses, and possibly by humans, but the rats of New York City surprisingly also have plenty to offer. A survey published in 2014 of the pathogens carried by rats trapped in houses and parks in Manhattan identified a huge burden of infectious agents in these animals, including several novel viruses. Among these are Norway rat hepaciviruses (NrHVs), which belong to the same family as hepatitis C virus (HCV). NrHVs were found in rat livers, raising the possibili...

Time course of collagen peak in bile duct-ligated rats

OpenAIRE

Tarcin, Orhan; Basaranoglu, Metin; Tahan, Veysel; Tahan, Gülgün; Sücüllü, Ilker; Yilmaz, Nevin; Sood, Gagan; Snyder, Ned; Hilman, Gilbert; Celikel, Cigdem; Tözün, Nurdan

2011-01-01

Abstract Background One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4-wk bile duct-ligated model is suitable in animal fibrogenesis trials. Methods Of the 53 male Wistar rats, 8 (Group 0) were used as a healthy control group. Bile duct...

Glucose turnover during insulin-induced hypoglycemia in liver-denervated rats

DEFF Research Database (Denmark)

Mikines, K J; Sonne, B; Richter, Erik

1985-01-01

The role of hepatic autonomic nerves in glucose production during hypoglycemia was studied. Selective, surgical denervation of the liver was performed in rats, which reduced hepatic norepinephrine concentrations by 96%. Hypoglycemia was induced by 250 mU of insulin intra-arterially in anesthetized...... as well as in chronically catheterized, awake rats. Half of the anesthetized denervated or sham-operated rats had previously been adrenodemedullated. Glucose turnover was measured by primed, constant intravenous infusion of [3-3H]glucose. Before as well as during hypoglycemia the arterial glucose...

Concentration of hepatic vitamins A and E in rats exposed to chlorpyrifos and/or enrofloxacin.

Science.gov (United States)

Spodniewska, A; Barski, D

2016-01-01

The aim of the study was to determine the level of antioxidant vitamins A and E in the liver of rats exposed to chlorpyrifos and/or enrofloxacin. Chlorpyrifos (Group I) was administered at a dose of 0.04 LD50 (6 mg/kg b.w.) for 28 days, and enrofloxacin (Group II) at a dose of 5 mg/kg b.w. for 5 consecutive days. The animals of group III were given both of the mentioned above compounds at the same manner as groups I and II, but enrofloxacin was applied to rats for the last 5 days of chlorpyrifos exposure (i.e. on day 24, 25, 26, 27 and 28). Chlorpyrifos and enrofloxacin were administered to rats intragastrically via a gastric tube. The quantitative determination of vitamins was made by the HPLC method. The results of this study indicated a reduction in the hepatic concentrations of vitamins A and E, compared to the control, which sustained for the entire period of the experiment. The four-week administration of chlorpyrifos to rats resulted in a significant decrease of vitamins in the initial period of the experiment, i.e. up to 24 hours after exposure. For vitamin A the maximum drop was observed after 24 hours (19.24%) and for vitamin E after 6 hours (23.19%). Enrofloxacin caused a slight (3-9%) reduction in the level of the analysed vitamins. In the chlorpyrifos-enrofloxacin co-exposure group reduced vitamins A and E levels were also noted, but changes in this group were less pronounced in comparison to the animals intoxicated with chlorpyrifos only. The decrease in the antioxidant vitamin levels, particularly noticeable in the chlorpyrifos- and the chlorpyrifos combined with enrofloxacin-treated groups, may result not only from the increase in the concentration of free radicals, but also from the intensification of the secondary stages of lipid peroxidation.

Ethanolic Extract of Butea monosperma Leaves Elevate Blood Insulin Level in Type 2 Diabetic Rats, Stimulate Insulin Secretion in Isolated Rat Islets, and Enhance Hepatic Glycogen Formation

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Mehdi Bin Samad

2014-01-01

Full Text Available We measured a vast range of parameters, in an attempt to further elucidate previously claimed antihyperglycemic activity of Butea monosperma. Our study clearly negates the possibility of antidiabetic activity by inhibited gastrointestinal enzyme action or by reduced glucose absorption. Reduction of fasting and postprandial glucose level was reconfirmed (P<0.05. Improved serum lipid profile via reduced low density lipoprotein (LDL, cholesterol, triglycerides (TG, and increased high density lipoprotein (HDL was also reestablished (P<0.05. Significant insulin secretagogue activity of B. monosperma was found in serum insulin assay of B. monosperma treated type 2 diabetic rats (P<0.01. This was further ascertained by our study on insulin secretion on isolated rat islets (P<0.05. Improved sensitivity of glucose was shown by the significant increase in hepatic glycogen deposition (P<0.05. Hence, we concluded that antihyperglycemic activity of B. monosperma was mediated by enhanced insulin secretion and enhanced glycogen formation in the liver.

Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy

Science.gov (United States)

Dadsetan, Sherry; Balzano, Tiziano; Forteza, Jerónimo; Cabrera-Pastor, Andrea; Taoro-Gonzalez, Lucas; Hernandez-Rabaza, Vicente; Gil-Perotín, Sara; Cubas-Núñez, Laura; García-Verdugo, José-Manuel; Agusti, Ana; Llansola, Marta; Felipo, Vicente

2016-01-01

Inflammation contributes to cognitive impairment in patients with hepatic encephalopathy (HE). However, the process by which peripheral inflammation results in cognitive impairment remains unclear. In animal models, neuroinflammation and altered neurotransmission mediate cognitive impairment. Taking into account these data, we hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering AMPA and/or NMDA receptors membrane expression; (3) reducing peripheral inflammation with infliximab (anti-TNF-a) would improve spatial learning; (4) this would be associated with reduced neuroinflammation and normalization of the membrane expression of glutamate receptors. The aims of this work were to assess these hypotheses. We analyzed in rats with portacaval shunt (PCS) and control rats, treated or not with infliximab: (a) peripheral inflammation by measuring prostaglandin E2, IL10, IL-17, and IL-6; (b) neuroinflammation in hippocampus by analyzing microglial activation and the content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; and (d) spatial learning in the Radial and Morris water mazes. We assessed the effects of treatment with infliximab on peripheral inflammation, on neuroinflammation and AMPA and NMDA receptors membrane expression in hippocampus and on spatial learning and memory. PCS rats show increased serum prostaglandin E2, IL-17, and IL-6 and reduced IL-10 levels, indicating increased peripheral inflammation. PCS rats also show microglial activation and increased nuclear NF-kB and expression of TNF-a and IL-1b in hippocampus. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory in the radial and Morris water maze. Treatment with infliximab reduces peripheral inflammation in PCS rats, normalizing prostaglandin E2, IL-17, IL-6, and

CONTRIBUTION OF LIVER NERVES, GLUCAGON, AND ADRENALINE TO THE GLYCEMIC RESPONSE TO EXERCISE IN RATS

NARCIS (Netherlands)

VAN DIJK, G; BALKAN, B; LINDFELDT, J; BOUWS, G; SCHEURINK, AJW; AHREN, B; STEFFENS, AB

The contribution of hepatic sympathetic innervation, glucagon and adrenaline to the glycaemic response to exercise was investigated in rats. Hepatically denervated (LDX) or sham operated (SHAM) rats with permanent catheters were therefore submitted to swimming with or without infusion of

Contribution of liver nerves, glucagon, and adrenaline to the glycaemic response to exercise in rats

NARCIS (Netherlands)

van Dijk, Gertjan; Balkan, B.; Lindfeldt, J.; Bouws, G.; Scheurink, A.J.W.; Ahrén, B.; Steffens, A.B.

1994-01-01

The contribution of hepatic sympathetic innervation, glucagon and adrenaline to the glycaemic response to exercise was investigated in rats. Hepatically denervated (LDX) or sham operated (SHAM) rats with permanent catheters were therefore submitted to swimming with or without infusion of

[Changes in serotonin and noradrenaline in hepatic encephalopathy as a result of liver failure in rat].

Science.gov (United States)

Song, Min-ning; Song, Yu-na; Chen, Fu; Luo, Mei-lan

2007-01-01

To investigate the changes in serotonin (5-HT) and noradrenaline (NA) in hepatic encephalopathy as a result of acute and chronic liver failure in rat. One hundred and ten Sprague-Dawley (SD) rats were randomly divided into groups of normal control (n=20), experimental group of acute liver failure (ALF) encephalopathy (n=45), and experimental group of chronic liver failure (CLF) encephalopathy (n=45). Two dosages of thioacetamide (TAA) of 500 mg/kg were gavaged with an interval of 24 hours to reproduce ALF model. To reproduce CLF model rats were fed with 0.03% TAA in drinking water for 10 weeks, and 50% of TAA dosage was added or withheld according to the change in weekly body weight measurement. Animals were sacrificed and venous blood specimens were obtained after successful replication of model, and 5-HT, NA, ammonia, parameters of liver function were determined, and liver and brain were studied pathologically. The experiment showed that the liver functions of rats in groups ALF encephalopathy and CLF encephalopathy deteriorated seriously, changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumen (ALB), ALB/globulin (A/G), and blood ammonia were observed(Pliver and brain pathologies were identical to those of ALF and CLF encephalopathy. The values of 5-HT were increased in groups ALF encephalopathy and CLF encephalopathy [(16.06+/-1.08) micromol/L and (15.32+/-1.48) micromol/L] compared with the normal group [(2.75+/-0.26) micromol/L, both Pencephalopathy [(94.0+/-2.13) pmol/L vs.(121.2+/-14.8) pmol/L,Pencephalopathy and CLF encephalopathy. The content of NA decreases remarkably in CLF encephalopathy.

Lipidomic and Antioxidant Response to Grape Seed, Corn and Coconut Oils in Healthy Wistar Rats

Directory of Open Access Journals (Sweden)

Abraham Wall-Medrano

2017-01-01

Full Text Available Specialty oils differ in fatty acid, phytosterol and antioxidant content, impacting their benefits for cardiovascular health. The lipid (fatty acid, phytosterol and antioxidant (total phenolics, radical scavenging capacity profiles of grapeseed (GSO, corn (CO and coconut (CNO oils and their physiological (triacylglycerides, total and HDL-cholesterol and antioxidant capacity (FRAP in serum and fatty acid and phytosterol hepatic deposition and genomic (HL, LCAT, ApoA-1 and SR-BP1 mRNA hepatic levels responses after their sub-chronic intake (10% diet for 28 days was examined in healthy albino rats. Fatty acid, phytosterol and antioxidant profiles differed between oils (p ≤ 0.01. Serum and hepatic triacylglycerides and total cholesterol increased (p ≤ 0.01; serum HDL-Cholesterol decreased (p < 0.05; but serum FRAP did not differ (p > 0.05 in CNO-fed rats as compared to CO or GSO groups. Hepatic phytosterol deposition was higher (+2.2 mg/g; p ≤ 0.001 in CO- than GSO-fed rats, but their fatty acid deposition was similar. All but ApoA-1 mRNA level increased in GSO-fed rats as compared to other groups (p ≤ 0.01. Hepatic fatty acid handling, but not antioxidant response, nor hepatic phytosterol deposition, could be related to a more efficient reverse-cholesterol transport in GSO-fed rats as compared to CO or CNO.

A new technique for labeling of Lipiodol with 188Re in the treatment of hepatic tumor

International Nuclear Information System (INIS)

Shyh-Jen Wang; Wan-Yu Lin; Bor-Tsung Hsieh; Kai-Yuan Cheng; Lie-Hang Shen; Ming-Ja Su

2004-01-01

A new method for the synthesis of 188 Re-Lipiodol without using a chelating agent and to evaluate the stability and biodistribution of the new agent in rats with hepatic tumors was attempted. Eighteen male Sprague -Dawley rats with liver tumors were sacrificed at 1, 24, and 48 hours (six rats at each time) after injection of approximately 7.4 MBq (0.2 mCi) of 188 Re Lipiodol via the hepatic artery. Samples of tumor, liver and other organs were collected and tissue concentration (%ID/g) of the markers were calculated. A high level of radioactivity in the hepatic tumors was found at every time of the study. The ratios of tumor to normal liver tissue concentration (T/N ratio) were 7.62 at 1 hour, 8.03 at 24 hours, and 7.70 at 48 hours. Except for the liver, kidneys and lungs, concentrations in other organs were low. The new method for labeling Lipiodol with 188 Re is simple and has potential for the treatment of hepatic tumors. (author)

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

Defatted Kenaf (Hibiscus cannabinus L. Seed Meal and Its Phenolic-Saponin-Rich Extract Protect Hypercholesterolemic Rats against Oxidative Stress and Systemic Inflammation via Transcriptional Modulation of Hepatic Antioxidant Genes

Directory of Open Access Journals (Sweden)

Kim Wei Chan

2018-01-01

Full Text Available The present study aimed to investigate the antioxidant and anti-inflammatory properties of defatted kenaf seed meal (DKSM and its phenolic-saponin-rich extract (PSRE in hypercholesterolemic rats. Hypercholesterolemia was induced using atherogenic diet feeding, and dietary interventions were conducted by incorporating DKSM (15% and 30% or PSRE (at 2.3% and 4.6%, resp., equivalent to the total content of DKSM-phenolics and saponins in the DKSM groups into the atherogenic diets. After ten weeks of intervention, serum total antioxidant capacities of hypercholesterolemic rats were significantly enhanced by DKSM and PSRE supplementation (p<0.05. Similarly, DKSM and PSRE supplementation upregulated the hepatic mRNA expression of antioxidant genes (Nrf2, Sod1, Sod2, Gsr, and Gpx1 of hypercholesterolemic rats (p<0.05, except for Gpx1 in the DKSM groups. The levels of circulating oxidized LDL and proinflammatory biomarkers were also markedly suppressed by DKSM and PSRE supplementation (p<0.05. In aggregate, DKSM and PSRE attenuated the hypercholesterolemia-associated oxidative stress and systemic inflammation in rats, potentially by enhancement of hepatic endogenous antioxidant defense via activation of the Nrf2-ARE pathway, which may be contributed by the rich content of phenolics and saponins in DKSM and PSRE. Hence, DKSM and PSRE are prospective functional food ingredients for the potential mitigation of atherogenic risks in hypercholesterolemic individuals.

Defatted Kenaf (Hibiscus cannabinus L.) Seed Meal and Its Phenolic-Saponin-Rich Extract Protect Hypercholesterolemic Rats against Oxidative Stress and Systemic Inflammation via Transcriptional Modulation of Hepatic Antioxidant Genes

Science.gov (United States)

Mohamed Alitheen, Noorjahan Banu; Ooi, Der Jiun; Khong, Nicholas M. H.

2018-01-01

The present study aimed to investigate the antioxidant and anti-inflammatory properties of defatted kenaf seed meal (DKSM) and its phenolic-saponin-rich extract (PSRE) in hypercholesterolemic rats. Hypercholesterolemia was induced using atherogenic diet feeding, and dietary interventions were conducted by incorporating DKSM (15% and 30%) or PSRE (at 2.3% and 4.6%, resp., equivalent to the total content of DKSM-phenolics and saponins in the DKSM groups) into the atherogenic diets. After ten weeks of intervention, serum total antioxidant capacities of hypercholesterolemic rats were significantly enhanced by DKSM and PSRE supplementation (p < 0.05). Similarly, DKSM and PSRE supplementation upregulated the hepatic mRNA expression of antioxidant genes (Nrf2, Sod1, Sod2, Gsr, and Gpx1) of hypercholesterolemic rats (p < 0.05), except for Gpx1 in the DKSM groups. The levels of circulating oxidized LDL and proinflammatory biomarkers were also markedly suppressed by DKSM and PSRE supplementation (p < 0.05). In aggregate, DKSM and PSRE attenuated the hypercholesterolemia-associated oxidative stress and systemic inflammation in rats, potentially by enhancement of hepatic endogenous antioxidant defense via activation of the Nrf2-ARE pathway, which may be contributed by the rich content of phenolics and saponins in DKSM and PSRE. Hence, DKSM and PSRE are prospective functional food ingredients for the potential mitigation of atherogenic risks in hypercholesterolemic individuals. PMID:29849908

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

Science.gov (United States)

Assy, Nimer; Grozovski, Masha; Bersudsky, Ilana; Szvalb, Sergio; Hussein, Osamah

2006-01-01

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD). METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M+R), ezetimibe (2 mg/kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG (+1263%, P < 0.001), hepatic cholesterol (+245%, P < 0.03), hepatic MDA levels (+225%, P < 0.001), serum TNF-alpha (17.8 ± 10 vs 7.8 ± 0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P < 0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol (+443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin. PMID:16865780

[Morphologic characteristic of chronic toxic hepatitis for treatment with Neoselen].

Science.gov (United States)

Isroilov, R I; Salikhodzhaeva, U Sh

2011-01-01

The purpose of the given research work was to study the features of morphologic changes arising for treatment of chronic hepatitis with Neoselen. It was established a picture of chronic active hepatitis in the liver of rats with the following development of chronic persisting hepatitis by the 40 daily administration of heliotrine and its transmission into cirrhosis in a certain part of animals. Hepatic cirrhosis has a small nodal portal character by its pathognomonic morphologic signs. A noticeable remittance of destructive necrotic changes in hepatic parenchymatous elements and reduction in a volume of proliferative inflammatory infiltration with an acceleration in process of its fibrozation in only periportal zones of hepatic lobules found to be for treatment of chronic hepatitis with Neoselen. That prevents from transmission of chronic hepatitis into cirrhosis in a greater part of animals that is a morphologic evidence of importance of selenium in a restorative process of biologic membranes and its involvement in a remittance process of destructive and inflammatory changes in the liver and prevention from development of agressive hepatitis and its transmission into cirrhosis.

Diverse structural approaches to haem appropriation by pathogenic bacteria.

Science.gov (United States)

Hare, Stephen A

2017-04-01

The critical need for iron presents a challenge for pathogenic bacteria that must survive in an environment bereft of accessible iron due to a natural low bioavailability and their host's nutritional immunity. Appropriating haem, either direct from host haemoproteins or by secreting haem-scavenging haemophores, is one way pathogenic bacteria can overcome this challenge. After capturing their target, haem appropriation systems must remove haem from a high-affinity binding site (on the host haemoprotein or bacterial haemophore) and transfer it to a binding site of lower affinity on a bacterial receptor. Structural information is now available to show how, using a combination of induced structural changes and steric clashes, bacteria are able to extract haem from haemophores, haemopexin and haemoglobin. This review focuses on structural descriptions of these bacterial haem acquisition systems, summarising how they bind haem and their target haemoproteins with particularly emphasis on the mechanism of haem extraction. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

Spondias mombin L. (Anacardiaceae) enhances detoxification of hepatic and macromolecular oxidants in acetaminophen-intoxicated rats.

Science.gov (United States)

Saheed, Sabiu; Taofik, Sunmonu Olatunde; Oladipo, Ajani Emmanuel; Tom, Ashafa Anofi Omotayo

2017-11-01

Oxidative stress is a common pathological condition associated with drug-induced hepatotoxicity. This study investigated Spondias mombin L. aqueous leaf extract on reactive oxygen species and acetaminophen-mediated oxidative onslaught in rats' hepatocytes. Hepatotoxic rats were orally administered with the extract and vitamin C for 4 weeks. The extract dose-dependently scavenged DPPH, hydrogen peroxide and hydroxyl radicals, with IC 50 values of 0.13, 0.66, and 0.64 mg/mL, and corresponding % inhibitions of 89, 80, and 90%, respectively at 1.0 mg/mL. Ferric ion was also significantly reduced. The marked (p<0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were reduced following treatment with the extract. The extract also significantly (p<0.05) induced the activities of antioxidant enzymes. These inductions reversed the acetaminophen-enhanced reduction in the specific activities of these enzymes as well as attenuated the observed elevated concentrations of autooxidized products and rived DNA in the acetaminophen-intoxicated animals. The observed effects competed with those of vitamin C and are suggestive of hepatoprotective and antioxidative attributes of the extract. Overall, the data from the present findings suggest that S. Mombin aqueous leaf extract is capable of ameliorating acetaminophen-mediated oxidative hepatic damage via enhancement of antioxidant defense systems.

Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats.

Science.gov (United States)

Mostafa, Rasha E; Salama, Abeer A A; Abdel-Rahman, Rehab F; Ogaly, Hanan A

2017-05-01

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.

Effects of carbon dioxide pneumoperitoneum on hepatic function in obstructive jaundice: an experimental study in a rat model.

Science.gov (United States)

Bostanci, Erdal Birol; Yol, Sinan; Teke, Zafer; Kayaalp, Cuneyt; Sakaogullari, Zisan; Ozel Turkcu, Ummuhani; Bilgihan, Ayse; Akoglu, Musa

2010-08-01

The physiology of the patient during laparoscopy differs from that of open surgery. Both pneumoperitoneum and obstructive jaundice impair the hepatic function, but the combined insult has not been previously examined. In this study, we aimed to investigate the effects of carbon dioxide (CO(2)) pneumoperitoneum on hepatic function in a rat model of obstructive jaundice. Forty-four male Sprague-Dawley rats were divided into four groups: group 1 (n = 10), sham-operated group; group 2 (n = 12), obstructive jaundice group; group 3 (n = 10), CO(2) pneumoperitoneum group; and group 4 (n = 12), obstructive jaundice and CO(2) pneumoperitoneum group. Common bile duct was ligated and divided in the obstructive jaundice groups. After 6 days, a 12-mmHg pneumoperitoneum was induced, maintained for 60 min, and released for 120 min. Blood samples were drawn for the measurement of white blood cell and platelet counts, serum liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin). Tissue samples were obtained for analyses of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels. We evaluated the degree of liver injury on a grading scale from 0 to 4, histopathologically. Pneumoperitoneum after biliary obstruction resulted in an increase in AST and ALT levels and a decrease in white blood cell and platelet counts. However, changes in liver tissue MDA, GSH, and SOD levels did not correlate with the changes in AST and ALT levels and white blood cell and platelet counts. After sham operation with pneumoperitoneum, the GSH levels in liver homogenate were significantly decreased in the group 3 when compared to the group 2. On the other hand, obstructive jaundice itself caused significant reduction in the SOD activity of liver homogenate in comparison to the group 3. Histopathologically, sinusoidal congestion and vacuolization were more severe in the group 3. Alterations in hepatic function occur in pneumoperitoneum applied

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

Science.gov (United States)

Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo-Yeon; Kim, Gyu Hee; Lee, DaeYeon; Lee, Yoo Jeong; Song, Eun Hyun; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won-Ho

2017-08-01

Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for

Use of deuterium labelled glucose in evaluating the pathway of hepatic glycogen synthesis

International Nuclear Information System (INIS)

Goodman, M.N.; Masuoka, L.K.; deRopp, J.S.; Jones, A.D.

1989-01-01

Deuterium labelled glucose has been used to study the pathway of hepatic glycogen synthesis during the fasted-refed transition in rats. Deuterium enrichment of liver glycogen was determined using nuclear magnetic resonance as well as mass spectroscopy. Sixty minutes after oral administration of deuterated glucose to fasted rats, the portal vein blood was fully enriched with deuterated glucose. Despite this, less than half of the glucose molecules incorporated into liver glycogen contained deuterium. The loss of deuterium label from glucose is consistent with hepatic glycogen synthesis by an indirect pathway requiring prior metabolism of glucose. The use of deuterium labelled glucose may prove to be a useful probe to study hepatic glycogen metabolism. Its use may also find application in the study of liver glycogen metabolism in humans by a noninvasive means

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats.

Science.gov (United States)

Axen, Kathleen V; Axen, Kenneth

2006-08-01

The effects of a very low-carbohydrate (VLC), high-fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high-carbohydrate (HC), low-fat (LF) regimen in dietary obese rats. Male Sprague-Dawley rats, made obese by 8 weeks ad libitum consumption of an HF diet, developed features of the metabolic syndrome vs. lean control (C) rats, including greater visceral, subcutaneous, and hepatic fat masses, elevated plasma cholesterol levels, impaired glucose tolerance, and fasting and post-load insulin resistance. Half of the obese rats (VLC) were then fed a popular VLC-HF diet (Weeks 9 and 10 at 5% and Weeks 11 to 14 at 15% carbohydrate), and one-half (HC) were pair-fed an HC-LF diet (Weeks 9 to 14 at 60% carbohydrate). Energy intakes of pair-fed VLC and HC rats were less than C rats throughout Weeks 9 to 14. Compared with HC rats, VLC rats exhibited impaired insulin and glycemic responses to an intraperitoneal glucose load at Week 10 and lower plasma triacylglycerol levels but retarded loss of hepatic, retroperitoneal, and total body fat at Week 14. VLC, HC, and C rats no longer differed in body weight, plasma cholesterol, glucose tolerance, or fasting insulin resistance at Week 14. Progressive decreases in fasting insulin resistance in obese groups paralleled concomitant reductions in hepatic, retroperitoneal, and total body fat. When energy intake was matched, the VLC-HF diet provided no advantage in weight loss or in improving those components of the metabolic syndrome induced by dietary obesity and may delay loss of hepatic and visceral fat as compared with an HC-LF diet.

Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin:cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide.

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Svetlov, S I; Sturm, E; Olson, M S; Crawford, J M

1999-07-01

Normal rat bile contains secretory platelet-activating factor acetylhydrolase (PAF-AH), the enzyme capable of hydrolyzing the inflammatory mediator platelet-activating factor (PAF), and phospholipids containing oxidized truncated fatty acids. Because lecithin:cholesterol acyltransferase (LCAT) possesses intrinsic PAF-AH-like activity, it also may represent a potential anti-inflammatory enzyme. The behavior of PAF-AH and LCAT in hepatobiliary inflammatory responses in vivo has not been characterized. We therefore investigated the biliary and plasma secretion and pharmacological characteristics of these enzymes in rats subjected to intraportal bacterial endotoxin exposure (lipopolysaccharide [LPS], Escherichia coli, 055:B5). Portal vein LPS infusion (1 mg/kg, bolus) resulted in a maximal 4- to 5-fold increase in bile PAF-AH-specific activity with a gradual decline to baseline by 18 hours. Biliary PAF-AH hydrolyzed also the truncated sn-2-succinoyl and sn-2-glutaroyl analogs of PAF, indicating a broader activity of PAF-AH in bile toward byproducts of glycerophospholipid peroxidation. Plasma PAF-AH activity was not altered 5 hours after LPS injection compared with saline injection, but it was significantly elevated 18 hours after endotoxin exposure. The levels of LCAT in bile were low and declined to nearly undetectable values by 5 hours after cannulation in both control and LPS-exposed rats. Plasma LCAT activity was significantly increased after 5 hours and decreased 18 hours after LPS injection. In summary, hepatic exposure to endotoxin results in a rapid increase in biliary secretion of PAF-AH followed by elevation of LCAT and PAF-AH levels in plasma. We propose that biliary secretion of PAF-AH may be involved in the hepatic response to endotoxic insult by counteracting potential inflammatory damage in the biliary tree and gastrointestinal tract, whereas plasma increases in LCAT and PAF-AH may promote elimination of excess PAF and oxidized phospholipids in the

High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation.

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Mock, Kaitlin; Lateef, Sundus; Benedito, Vagner A; Tou, Janet C

2017-01-01

High-fructose corn syrup-55 (HFCS-55) has been suggested to be more lipogenic than sucrose, which increases the risk for nonalcoholic fatty liver disease (NAFLD) and dyslipidemia. The study objectives were to determine the effects of drinking different sugar-sweetened solutions on hepatic gene expression in relation to liver fatty acid composition and risk of NAFLD. Female rats were randomly assigned (n=7 rats/group) to drink water or water sweetened with 13% (w/v) HFCS-55, sucrose or fructose for 8 weeks. Rats drinking HFCS-55 solution had the highest (P=.03) hepatic total lipid and triglyceride content and histological evidence of fat infiltration. Rats drinking HFCS-55 solution had the highest hepatic de novo lipogenesis indicated by the up-regulation of stearoyl-CoA desaturase-1 and the highest (Ptriglyceride-rich lipoprotein from the liver was increased as shown by up-regulation of gene expression of microsomal triglyceride transfer protein in rats drinking sucrose, but not HFCS-55 solution. The observed lipogenic effects were attributed to the slightly higher fructose content of HFCS-55 solution in the absence of differences in macronutrient and total caloric intake between rats drinking HFCS-55 and sucrose solution. Results from gene expression and fatty acid composition analysis showed that, in a hypercaloric state, some types of sugars are more detrimental to the liver. Based on these preclinical study results, excess consumption of caloric sweetened beverage, particularly HFCS-sweetened beverages, should be limited. Published by Elsevier Inc.

Duodenal-jejunal bypass surgery up-regulates the expression of the hepatic insulin signaling proteins and the key regulatory enzymes of intestinal gluconeogenesis in diabetic Goto-Kakizaki rats.

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Sun, Dong; Wang, Kexin; Yan, Zhibo; Zhang, Guangyong; Liu, Shaozhuang; Liu, Fengjun; Hu, Chunxiao; Hu, Sanyuan

2013-11-01

Duodenal-jejunal bypass (DJB), which is not routinely applied in metabolic surgery, is an effective surgical procedure in terms of type 2 diabetes mellitus resolution. However, the underlying mechanisms are still undefined. Our aim was to investigate the diabetic improvement by DJB and to explore the changes in hepatic insulin signaling proteins and regulatory enzymes of gluconeogenesis after DJB in a non-obese diabetic rat model. Sixteen adult male Goto-Kakizaki rats were randomly divided into DJB and sham-operated groups. The body weight, food intake, hormone levels, and glucose metabolism were measured. The levels of protein expression and phosphorylation of insulin receptor-beta (IR-β) and insulin receptor substrate 2 (IRS-2) were evaluated in the liver. We also detected the expression of key regulatory enzymes of gluconeogenesis [phosphoenoylpyruvate carboxykinase-1 (PCK1), glucose-6-phosphatase-alpha (G6Pase-α)] in small intestine and liver. DJB induced significant diabetic improvement with higher postprandial glucagons-like peptide 1, peptide YY, and insulin levels, but without weight loss. The DJB group exhibited increased expression and phosphorylation of IR-β and IRS-2 in liver, up-regulated the expression of PCK1 and G6Pase-α in small intestine, and down-regulated the expression of these enzymes in liver. DJB is effective in up-regulating the expression of the key proteins in the hepatic insulin signaling pathway and the key regulatory enzymes of intestinal gluconeogenesis and down-regulating the expression of the key regulatory enzymes of hepatic gluconeogenesis without weight loss. Our study helps to reveal the potential role of hepatic insulin signaling pathway and intestinal gluconeogenesis in ameliorating insulin resistance after metabolic surgery.

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.

High-fat diet enhanced retinal dehydrogenase activity, but suppressed retinol dehydrogenase activity in liver of rats

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Mian Zhang

2015-04-01

Full Text Available Evidence has shown that hyperlipidemia is associated with retinoid dyshomeostasis. In liver, retinol is mainly oxidized to retinal by retinol dehydrogenases (RDHs and alcohol dehydrogenases (ADHs, further converted to retinoic acid by retinal dehydrogenases (RALDHs. The aim of this study was to investigate whether high-fat diet (HFD induced hyperlipidemia affected activity and expression of hepatic ADHs/RDHs and RALDHs in rats. Results showed that retinol levels in liver, kidney and adipose tissue of HFD rats were significantly increased, while plasma retinol and hepatic retinal levels were markedly decreased. HFD rats exhibited significantly downregulated hepatic ADHs/RDHs activity and Adh1, Rdh10 and Dhrs9 expression. Oppositely, hepatic RALDHs activity and Raldh1 expression were upregulated in HFD rats. In HepG2 cells, treatment of HFD rat serum inhibited ADHs/RDHs activity and induced RALDHs activity. Among the tested abnormally altered components in HFD rat serum, cholesterol reduced ADHs/RDHs activity and RDH10 expression, while induced RALDHs activity and RALDH1 expression in HepG2 cells. Contrary to the effect of cholesterol, cholesterol-lowering agent pravastatin upregulated ADHs/RDHs activity and RDH10 expression, while suppressed RALDHs activity and RALDH1 expression. In conclusion, hyperlipidemia oppositely altered activity and expression of hepatic ADHs/RDHs and RALDHs, which is partially due to the elevated cholesterol levels.

Effects of parenteral infusion with medium-chain triglycerides and safflower oil emulsions on hepatic lipids, plasma amino acids and inflammatory mediators in septic rats.

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Yeh, S; Chao, C; Lin, M; Chen, W

2000-04-01

This study was designed to investigate the effects of preinfusion with total parenteral nutrition (TPN) using medium-chain triglycerides (MCT) versus safflower oil (SO) emulsion as fat sources on hepatic lipids, plasma amino acid profiles, and inflammatory-related mediators in septic rats. Normal rats, with internal jugular catheters, were divided into two groups and received TPN. TPN provided 300kcal/kg/day with 40% of the non-protein energy provided as fat. All TPN solutions were isonitrogenous and identical in nutrient composition except for the fat emulsion, which was made of SO or a mixture of MCT and soybean oil (9:1) (MO). After receiving TPN for 6 days, each group of rats was further divided into control and sepsis subgroups. Sepsis was induced by cecal ligation and puncture, whereas control rats received sham operation. All rats were classified into four groups as follows: MCT control group (MOC, n= 8), MCT sepsis group (MOS, n= 8), safflower oil control group (SOC, n= 8), and safflower oil sepsis group (SOS, n= 11). The results of the study demonstrated that the MOS group had lower hepatic lipids than did the SOS group. Plasma leucine and isoleucine levels were significantly lower in the SOS than in the SOC group, but no differences in these two amino acids were observed between the MOC and MOS groups. Plasma arginine levels were significantly lower in septic groups than in those without sepsis despite whether MCT or safflower oil was infused. Plasma glutamine and alanine levels, however, did not differ between septic and non-septic groups either in the SO or MO groups. No differences in interleukin-1b, interleukin-6, tumor necrosis factor-alpha, and leukotriene B(4)concentrations in peritoneal lavage fluid were observed between the two septic groups. These results suggest that catabolic reaction is septic rats preinfused MCT is not as obvious as those preinfused safflower oil. Compared with safflower oil, TPN with MCT administration has better effects on

Increased hepatic cholesterol esterification with essential fatty acid deficiency (EFAD): relationship to plasma lipoprotein (LP) cholesterol content

International Nuclear Information System (INIS)

Ney, D.M.; Ziboh, V.A.; Schneeman, B.O.

1986-01-01

EFAD in the rat is associated with hepatic accumulation of esterified cholesterol and altered distribution of cholesterol between plasma and hepatic tissue. Little is known regarding the impact of EFAD on LP composition. To determine the relationship between hepatic cholesterol esterification and plasma lP composition in control (C) and EFAD male Wistar rats, the authors induced EFAD with continuous intragastric (IG) infusion of EFA-free solutions containing 3.5% of calories as triolein for 7 and 14 days. C animals received IG infusion of solutions containing 3.5% of calories as linoleic acid. Data in the EFAD groups reveal: (i) marked decreases in hepatic EFAs and increases in monoenoic acids; (ii) progressive increases in hepatic content of triglyceride and esterified cholesterol with 7 and 14 days of feeding; (iii) assay of acyl CoA:cholesterol acyltransferase activity in hepatic tissue using 14 C-cholesterol demonstrates an increase in hepatic cholesterol esterification when compared to C animals. Increased hepatic cholesterol esterification correlates with elevated levels of esterified cholesterol in plasma VLDL and HDL particles. These data indicate that the elevated levels of cholesterol esters in LP particles is due, at least in part, to increased hepatic cholesterol esterification with EFAD

Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation

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Rojas, Jennifer M.; Bruinstroop, Eveline; Printz, Richard L.; Alijagic-Boers, Aldijana; Foppen, Ewout; Turney, Maxine K.; George, Leena; Beck-Sickinger, Annette G.; Kalsbeek, Andries; Niswender, Kevin D.

2015-01-01

Objective Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. Methods Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion. Results Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation. Conclusions These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is

Sapucaia nuts ( Lecythis pisonis ) modulate the hepatic ...

African Journals Online (AJOL)

Sapucaia nuts ( Lecythis pisonis ) modulate the hepatic inflammatory and antioxidant metabolism activity in rats fed high-fat diets. ... that “sapucaia” could serve as a potential source of antioxidants and as a protector agent for the examined animals. Keywords: Sapucaia nuts, inflammation, oxidative stress, gene expression ...

Alterations in sulfur and nitrogen metabolism in rats with portacaval shunts

International Nuclear Information System (INIS)

Benjamin, L.E.

1985-01-01

The effect of portacaval shunt (PCS) on methionine and cysteine metabolism was investigated. PCS rats excreted more urinary [ 35 S]sulfate and less [ 35 S]taurine than controls after injection of [ 35 S]methionine of [ 35 S]cysteine. Total urinary taurine excretion was unchanged. Under basal conditions PCS rats excreted more taurine than controls. Relative rates of transsulfuration in PCS and control rats were studied, and no difference in flux of 35 S from methionine to cysteine was found. Total hepatic activities of three transsulfuration pathway enzymes were also unchanged after PCS. In contrast, hepatic activities of three cysteine-oxidizing enzymes were depressed after PCS, suggesting that changes in hepatic metabolism after PCS are selective. PCS rats fed a high (60%) casein diet ate less and took longer to recover their preoperative body weight than controls. All PCS rats had higher plasma ammonia and urinary orotic acid levels than controls. Increasing dietary protein elevated plasma ammonia and urinary orotic acid to a greater extent in PCS rats. After injection of [ 35 S]methionine or [ 35 S]cysteine, urinary 35 S and [ 35 S]sulfate excretion increased and [ 35 S]taurine an total taurine excretion decreased in all rats fed 60% casein, but the effect was greater in PCS rats. Changes in cysteine sulfinate decarboxylase activity in rats fed a high protein diet was examined. Activity decreased 95% in rats fed diets containing between 18 and 75% casein. The effect was observed after feeding a 60% casein diet for 2 days and was reversed when rats were refed an 18% casein diet

The phosphoinositide 3-kinase/Akt-signal pathway mediates proliferation and secretory function of hepatic sinusoidal endothelial cells in rats after partial hepatectomy

International Nuclear Information System (INIS)

Chen Ping; Zhang Lin; Ding Jiming; Zhu Jin; Li Ying; Duan Shigang; Yan Hongtao; Huan Yongwei; Dong Jiahong

2006-01-01

Objective: To investigate the role of AKT signaling pathway in hepatic sinusoidal endothelial cells (SECs) early after partial hepatectomy in rats and the regulatory mechanisms involved. Methods: The animal model of 70% hepatectomy was made. Hepatic SECs were isolated and cultured according to Braet et al.'s method with some modifications. The cultured hepatic SECs were divided into two groups: 70% partial hepatectomy groups and LY294002 group (LY). We observed the expressions of AKT and NF-κB in cultured hepatic SECs by Western blot, measured the levels of NO, NOs, IL-6, and HGF in the supernatants of hepatic SEC cultures and [ 3 H]thymidine incorporation, and analyzed cell cycle of cultured hepatic SECs by flow cytometer. The relationship of the Akt pathway with secretions and proliferation of hepatic SECs after partial hepatectomy was probed. Results: The levels of Akt protein expression increased significantly after partial hepatectomy in OG group and with a peak at 24 h post operation. Meanwhile, there was a markedly increase in phosphorylated Akt protein during 2-72 h after operation. But the expression and activity of Akt protein did not change significantly after partial hepatectomy in the LY group. So, partial hepatectomy can marked induce Akt expression and result in rapid and marked phosphorylation of Akt from 2 to 72 h thereafter. The changes of NF-κB expression in cultured hepatic SECs were similar to those of Akt expression after operation. The concentrations of HGF and IL-6 in the supernatants of cultured hepatic SECs were relatively low in the LY group, and were markedly increased after partial hepatectomy, with a peak at 24 h in the OG group. There were significant differences between the OG and LY groups at 6 and 24 h (P < 0.05). Both NO and NOS secretion was increased in the OG group compared to the LY group within 24 h after partial hepatectomy. But the secretion of NO and NOS was increased more markedly in the LY group than that in the OG

Hepatitis E: Discovery, global impact, control and cure.

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Khuroo, Mohammad S; Khuroo, Mehnaaz S; Khuroo, Naira S

2016-08-21

Hepatitis E was identified as an epidemic of non-A, non-B hepatitis from Kashmir, India in 1978. Hepatitis E virus (HEV), the etiological agent is the sole member of family Hepeviridae. The virus has marked heterogeneity and infects many animals like bats, camel, chicken, deer, boar, mongoose, pigs, rats, rabbit and cutthroat trout. Hepatitis E is a disease with a major global impact and has two distinct epidemiological patterns. Hepatitis E is an imperative health issue in developing nations, transmitted through sullied water and happens most every now in young adults. The disease is particularly severe during pregnancy and in people with underlying liver cirrhosis. Autochthonous hepatitis E is increasingly recognized in developed countries. The virus infects domestic pigs, wild boar and Sika deer in these countries. HEV infections in humans occur by eating the undercooked game flesh, raw liver from supermarkets and Figatelli sausages. Blood transfusion-associated HEV infections occur in many countries and screening of donors for HEV RNA is under consideration. Hepatitis E causes a number of extrahepatic diseases, including a wide spectrum of neurological syndromes. HEV genotype 3 causes prolonged viremia, chronic hepatitis, liver fibrosis and cirrhosis in organ transplant patients. The virus is amenable to ribavirin monotherapy and most patients clear the virus in a few weeks. Hepatitis E vaccine -239, marketed in China, has shown high efficacy with sustained protection for over four years.

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.

Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats.

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Ding, Shibin; Jiang, Jinjin; Zhang, Guofu; Bu, Yongjun; Zhang, Guanghui; Zhao, Xiangmei

2017-01-01

Studies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy. Eight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight. We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation

Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats.

Directory of Open Access Journals (Sweden)

Shibin Ding

Full Text Available Studies have demonstrated that resveratrol (a natural polyphenol and caloric restriction activate Sirtuin-1 (SIRT1 and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.Eight-week-old male Wistar rats (40 were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw; and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw and caloric restriction (30% partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30% and resveratrol (a pharmacological SIRT1 activator

Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria

Energy Technology Data Exchange (ETDEWEB)

Tseng, Michael T., E-mail: mttsen01@louisville.edu [Dept of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky (United States); Lu, Xiaoqin, E-mail: x0lu0003@louisville.edu [Dept of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky (United States); Duan, Xiaoxian, E-mail: x0duan02@louisville.edu [Dept of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky (United States); Hardas, Sarita S., E-mail: sarita.hardas@uky.edu [Dept. of Chemistry, University of Kentucky, Lexington, Kentucky (United States); Sultana, Rukhsana, E-mail: rsult2@uky.edu [Dept. of Chemistry, University of Kentucky, Lexington, Kentucky (United States); Wu, Peng, E-mail: peng.wu@uky.edu [Dept of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky (United States); Unrine, Jason M., E-mail: jason.unrine@uky.edu [Dept of Plant and Soil Sciences, University of Kentucky, Lexington, Kentucky (United States); Graham, Uschi, E-mail: graham@caer.uky.edu [Center for Applied Energy Research, University of Kentucky, Lexington, Kentucky (United States); Butterfield, D. Allan, E-mail: dabcns@uky.edu [Dept. of Chemistry, University of Kentucky, Lexington, Kentucky (United States); Grulke, Eric A., E-mail: eric.grulke@uky.edu [Dept of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky (United States); Yokel, Robert A., E-mail: ryokel@email.uky.edu [Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky (United States)

2012-04-15

Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3{sup +} T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures. -- Highlights: ► Time course study on nanoceria induced hepatic alterations in rats. ► Serum AST elevation indicated acute hepatotoxicity. ► Ceria is retained for up to 30 days in Kupffer cells

Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: role of hepatic triglyceride utilization.

Science.gov (United States)

Qasem, Rani J; Li, Jing; Tang, Hee Man; Browne, Veron; Mendez-Garcia, Claudia; Yablonski, Elizabeth; Pontiggia, Laura; D'Mello, Anil P

2015-04-01

We have previously demonstrated that protein restriction throughout gestation and lactation reduces liver triglyceride content in adult rat offspring. However, the mechanisms mediating the decrease in liver triglyceride content are not understood. The aim of the current study was to use a new group of pregnant animals and their offspring and determine the contribution of increased triglyceride utilization via the hepatic fatty-acid oxidation and triglyceride secretory pathways to the reduction in liver triglyceride content. Pregnant Sprague-Dawley rats received either a control or a low protein diet throughout pregnancy and lactation. Pups were weaned onto laboratory chow on day 28 and killed on day 65. Liver triglyceride content was reduced in male, but not female, low-protein offspring, both in the fed and fasted states. The reduction was accompanied by a trend towards higher liver carnitine palmitoyltransferase-1a activity, suggesting increased fatty-acid transport into the mitochondrial matrix. However, medium-chain acyl coenzyme A dehydrogenase activity within the mitochondrial matrix, expression of nuclear peroxisome proliferator activated receptor-α, and plasma levels of β-hydroxybutyrate were similar between low protein and control offspring, indicating a lack of change in fatty-acid oxidation. Hepatic triglyceride secretion, assessed by blocking peripheral triglyceride utilization and measuring serum triglyceride accumulation rate, and the activity of microsomal transfer protein, were similar between low protein and control offspring. Because enhanced triglyceride utilization is not a significant contributor, the decrease in liver triglyceride content in male low-protein offspring is likely due to alterations in liver fatty-acid transport or triglyceride biosynthesis. © 2015 Wiley Publishing Asia Pty Ltd.

Interfering RNA against PKC-α Inhibits TNF-α-induced IP3R1 Expression and Improves Glomerular Filtration Rate in Rats with Fulminant Hepatic Failure.

Science.gov (United States)

Wang, Dong-Lei; Dai, Wen-Ying; Wang, Wen; Wen, Ying; Zhou, Ying; Zhao, Yi-Tong; Wu, Jian; Liu, Pei

2018-01-10

We have reported that tumor necrosis factor- (TNF-α) is critical for reduction of glomerular filtration rate (GFR) in rats with fulminant hepatic failure (FHF). The present study aims to evaluate the underlying mechanisms of decreased GFR during acute hepatic failure. Rats with FHF induced by D-galactosamine plus lipopolysaccharide (GalN/LPS) were injected intravenously with recombinant lentivirus harboring shRNA against the protein kinase C-α (PKC-α) gene (Lenti-shRNA-PKC-α). GFR, serum levels of aminotransferases, creatinine, urea nitrogen, potassium, sodium, chloride, TNF-α and endothelin-1 (ET-1), as well as type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression in renal tissue were assessed. The effects of PKC-α silencing on TNF-α-induced IP3R1, specificity protein 1 (SP-1) and c-Jun N-terminal kinase (JNK) expression, as well as cytosolic calcium content were determined in glomerular mesangial cell (GMCs) with RNAi against PKC-α. Renal IP3R1 overexpression was abrogated by pre-treatment with Lenti-shRNA-PKC-α. The PKC- silence significantly improved the compromised GFR, reduced Cr levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. TNF-α treatment increased expression of PKC-α, IP3R1, specificity protein 1 (SP-1), JNK and p-JNK in GMCs, and increased Ca2+ release and binding activity of SP-1 to the IP3R1 promoter. These effects were blocked by transfection of siRNA against the PKC-α gene, and the PKC-α gene silence also restored cytosolic [Ca2+]i. RNAi targeting PKC-α inhibited TNF-α-induced IP3R1 overexpression, and in turn improved compromised GFR in the development of acute kidney injury during FHF in rats.

The Effect of Tribulus Terrestris Extract on Hepatic Complications Due to the Gelofen Consumption in Adult Female Rats

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Leila Hejazi

2016-09-01

Full Text Available Background & Objective: Gelofen is one of the anti-inflammatory drugs which is used to relieve the pain and reduce the inflammations. This drug has side effects on body's tissues. This study aimed to investigate the effect of Tribulus terrestris (Tt plant on hepatic transaminases due to the Gelofen consumption. Materials & Methods: In this experimental study 56 rats were divided into 7 groups of 8 rats, including control, sham and 4 experimental groups receiving Gelofen 400mg / kg, Tt extract 80 mg / kg, Tt extract 20mg / kg and Gelofen with 400mg / kg doses, Tt extract  40mg / kg  and Gelofen 400mg / kg, and Tt extract 80mg / kg  and Gelofen 400mg / kg. Gelofen was prescribed intraperitoneal and Tt was prescribed orally for 21 days. At the end of phlebotomizing the animals, alanine aminotransferase (ALT, aspartate aminotransferase (AST, and Anaplastic lymphoma kinase (ALK levels were measured, and the results were analyzed by ANOVA and Duncan tests. The significant difference in the data was considered P> 0/05. Results: The results showed that the transaminase concentration in the groups receiving Gelofen alone and with the Tt extract in doses of 20mg /kg and 40 mg /kg had a significant increase compared to the control group and the groups receiving Tt alone and Tt with the dose of 80mg/kg with Gelofen,had a significant decrease compared to the control and Gelofen alone groups (P> 0/05.  Conclusion: The results showed that the Tt extract led to prevent the negative effects of Gelofen on hepatic tissue in a dose-dependent manner and in result on the serum levels of liver transaminases.

Control of ketogenesis in the perfused rat liver by the sympathetic innervation

NARCIS (Netherlands)

Beuers, U.; BECKH, K.; JUNGERMANN, K.

1986-01-01

The regulation of ketogenesis by the hepatic nerves was investigated in the rat liver perfused in situ. Electrical stimulation of the hepatic nerves around the portal vein and the hepatic artery caused a reduction of basal ketogenesis owing to a decrease in acetoacetate release to 30% with

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.

Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring

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Clayton, Zoe E.; Vickers, Mark H.; Bernal, Angelica; Yap, Cassandra; Sloboda, Deborah M.

2015-01-01

Aim Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Methods Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Results Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Conclusions Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may

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.

Science.gov (United States)

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.

Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude.

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Gola, Shefali; Gupta, Asheesh; Keshri, Gaurav K; Nath, Madhu; Velpandian, Thirumurthy

2016-03-20

With studies indicative of altered drug metabolism and pharmacokinetics (DMPK) under high altitude (HA)-induced hypobaric hypoxia, consideration of better therapeutic approaches has continuously been aimed in research for HA related illness management. DMPK of drugs like ibuprofen may get affected under hypoxia which establishes the requirement of different therapeutic dose regimen to ensure safe and effective therapy at HA. This study examined the effects of the chronic hypobaric hypoxia (CHH) on hepatic DMPK of ibuprofen in rats. Experimental animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for CHH exposure (7 or 14 days) in decompression chamber and administered with ibuprofen (80 mg/kg, body weight, p.o.). Results demonstrated that CHH significantly altered PK variables of ibuprofen and activities of both phase-I and II hepatic metabolic enzymes as compared to the animals under normoxic conditions. Hepatic histopathological observations also revealed marked alterations. Increase in pro-inflammatory cytokines/chemokines viz. IL-1β, IL-2, IFN-γ, TNF-α exhibited close relevance with diminished CYP2C9 expression under CHH. Moreover, the down-regulated CYP2C9 level further supported the underlying mechanism for reduced metabolism of ibuprofen and as a result, increased retention of parent drug in the system. Increased mean retention time, Vd, T½ of ibuprofen, and decreased AUC, Cmax and clearance during CHH further strengthened the present findings. In conclusion, CHH exposure significantly affects hepatic DMPK of ibuprofen, which may further influence the usual therapeutic dose-regimen. Further, there is requirement of human studies to evaluate their susceptibility toward hypobaric hypoxia. Copyright © 2016 Elsevier B.V. All rights reserved.

Biochemical properties of the plasma of rats with the experimentally induced hepatitis after oral administration of sodium diclofenac

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V. Gryshchenko

2017-04-01

Full Text Available We conducted an analysis of the metabolic activity of the liver and defined the peculiarities of biochemical parameters and macroelement composition of blood plasma of rats with experimentally induced toxic hepatitis. Hepatopathology was modeled by oral administration of sodium diclofenac at a dose of 12.5 mg/kg of body mass to rats during 14 days. For the preparation of plasma, rat blood was collected from the abdominal aorta into test-tubes with heparin, and then it was centrifuged at 1500 rev./min for 15–20 min. Then we studied biochemical parameters of blood indicators (level of total protein, albumin, total and conjugated bilirubin, glucose, creatinine, urea, triacylglycerols, cholesterol, thymol test value, activities of ALT, AST, LP and GGT, amylase and lipase and also its macroelement composition: concentration of sodium, potassium, phosphorus, calcium, magnesium and chlorine using automatic biochemical analyzer «BioSystem A15» (Spain according to the recommendations of the International Federation of Clinical Chemistry (IFCC Experts Panel. The results of the introduction in the laboratory rats of drug-induced toxic hepatitis indicate a decrease of metabolic activity of hepatocytes under this hepatopathology. The results showed a decrease in total protein by 17%, albumin by 11%, glucose by 6% , triacylglycerols by 53%, cholesterol by 54%, and an appreciable increase in thymol test value (by a factor of 2.8. Besides this, disruption of the liver pigment function, development of cytolytic syndrome and intrahepatic cholestasis were revealed in the affected animals. The increased activity of the studied blood enzymes (ALT by 28%, AST by 45%, LP by 30%, GGT by a factor of 2.1 confirmed these disruptions. The increase in AST/ALT by 12% ratio confirmed destructive changes in cell membranes, including mitochondrial membranes, caused by metabolic changes under the toxic influence of sodium diclofenac. The increased activities of α-amylase by

Actions of p-synephrine on hepatic enzyme activities linked to carbohydrate metabolism and ATP levels in vivo and in the perfused rat liver.

Science.gov (United States)

Maldonado, Marcos Rodrigues; Bracht, Lívia; de Sá-Nakanishi, Anacharis Babeto; Corrêa, Rúbia Carvalho Gomes; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

2018-01-01

p-Synephrine is one of the main active components of the fruit of Citrus aurantium (bitter orange). Extracts of the bitter orange and other preparations containing p-synephrine have been used worldwide to promote weight loss and for sports performance. The purpose of the study was to measure the action of p-synephrine on hepatic enzyme activities linked to carbohydrate and energy metabolism and the levels of adenine mononucleotides. Enzymes and adenine mononucleotides were measured in the isolated perfused rat liver and in vivo after oral administration of the drug (50 and 300 mg/kg) by using standard techniques. p-Synephrine increased the activity of glycogen phosphorylase in vivo and in the perfused liver. It decreased, however, the activities of pyruvate kinase and pyruvate dehydrogenase also in vivo and in the perfused liver. p-Synephrine increased the hepatic pools of adenosine diphosphate and adenosine triphosphate. Stimulation of glycogen phosphorylase is consistent with the reported increased glycogenolysis in the perfused liver and increased glycemia in rats. The decrease in the pyruvate dehydrogenase activity indicates that p-synephrine is potentially capable of inhibiting the transformation of carbohydrates into lipids. The capability of increasing the adenosine triphosphate-adenosine diphosphate pool indicates a beneficial effect of p-synephrine on the cellular energetics. Copyright © 2017 John Wiley & Sons, Ltd.

Infection of inbred rat strains with Rift Valley fever virus: development of a congenic resistant strain and observations on age-dependence of resistance.

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Anderson, G W; Rosebrock, J A; Johnson, A J; Jennings, G B; Peters, C J

1991-05-01

A congenic rat strain (WF.LEW) was derived from the susceptible Wistar-Furth (WF) (background strain) and the resistant LEW (donor strain) inbred strains and was used to evaluate the phenotypic expression of a dominant Mendelian gene that confers resistance to fatal hepatic disease caused by the ZH501 strain of Rift Valley fever virus (RVFV). Resistance to hepatic disease developed gradually with age, with full expression at approximately 10 weeks in the WF.LEW and LEW rat strains. The ZH501 strain caused fatal hepatitis in WF rats regardless of age. However, resistance to the SA75 RVFV strain (relatively non-pathogenic for adult rats), was age- and dose-dependent in both WF and LEW rats. The resistance gene transferred to the newly derived WF.LEW congenic rat strain appears to amplify age-dependent resistance of adult rats, resulting in protection against fatal hepatic disease caused by the virulent ZH501 strain. The congenic rat strain will be a valuable asset in elucidating the mechanism of resistance to Rift Valley fever virus governed by the dominant Mendelian gene.

Effects of betaine supplementation and choline deficiency on folate deficiency-induced hyperhomocysteinemia in rats.

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Liu, Ying; Liu, Yi-qun; Morita, Tatsuya; Sugiyama, Kimio

2012-01-01

The effect of betaine status on folate deficiency-induced hyperhomocysteinemia was investigated to determine whether folate deficiency impairs homocysteine removal not only by the methionine synthase (MS) pathway but also by the betaine-homocysteine S-methyltransferase (BHMT) pathway. For this purpose, we investigated the effect of dietary supplementation with betaine at a high level (1%) in rats fed a folate-deprived 10% casein diet (10C) and 20% casein diet (20C). We also investigated the effect of choline deprivation on folate deficiency-induced hyperhomocysteinemia in rats fed 20C. Supplementation of folate-deprived 10C and 20C with 1% betaine significantly suppressed folate deprivation-induced hyperhomocysteinemia, but the extent of suppression was partial or limited, especially in rats fed 10C, the suppression of plasma homocysteine increment being 48.5% in rats fed 10C and 69.7% in rats fed 20C. Although betaine supplementation greatly increased hepatic betaine concentration and BHMT activity, these increases did not fully explain why the effect of betaine supplementation was partial or limited. Folate deprivation markedly increased the hepatic concentration of N,N-dimethylglycine (DMG), a known inhibitor of BHMT, and there was a significant positive correlation between hepatic DMG concentration and plasma homocysteine concentration, suggesting that folate deficiency increases hepatic DMG concentration and thereby depresses BHMT reaction, leading to interference with the effect of betaine supplementation. Choline deprivation did not increase plasma homocysteine concentration in rats fed 20C, but it markedly enhanced plasma homocysteine concentration when rats were fed folate-deprived 20C. This indicates that choline deprivation reinforced folate deprivation-induced hyperhomocysteinemia. Increased hepatic DMG concentration was also associated with such an effect. These results support the concept that folate deficiency impairs homocysteine metabolism not only

Dietary taurine alters ascorbic acid metabolism in rats fed diets containing polychlorinated biphenyls.

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Mochizuki, H; Oda, H; Yokogoshi, H

2000-04-01

The effect of dietary taurine on ascorbic acid metabolism and hepatic drug-metabolizing enzymes was investigated in rats fed diets containing polychlorinated biphenyls (PCB) to determine whether taurine has an adaptive and protective function in xenobiotic-treated animals. Young male Wistar rats (60 g) were fed diets containing 0 or 0.2 g/kg diet PCB with or without 30 g/kg diet of taurine for 14 d. The rats fed the PCB-containing diets had greater liver weight, higher ascorbic acid concentrations in the liver and spleen and greater hepatic cytochrome P-450 contents than control rats that were not treated with PCB (P ascorbic acid excretion was enhanced, and serum cholesterol concentration (especially HDL-cholesterol) was significantly elevated compared with those in control rats. Dietary taurine significantly potentiated the increases in the urinary excretion of ascorbic acid and the rise in the levels of cytochrome P-450 which were caused by PCB treatment. On the other hand, the supplementation of taurine to control diet did not alter these variables. Taurine may enhance the hepatic drug-metabolizing systems, leading to the stimulation of the ascorbic acid metabolism in rats fed diets containing PCB.

Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection.

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Lenzi, M; Manotti, P; Muratori, L; Cataleta, M; Ballardini, G; Cassani, F; Bianchi, F B

1995-01-01

Within the multiform liver/kidney microsomal (LKM) family, a subgroup of sera that reacts with a liver cytosolic (LC) protein has been isolated and the new antigen-antibody system is called LC1. Unlike LKM antibody type 1 (anti-LKM1), anti-LC1 is said to be unrelated to hepatitis C virus (HCV) infection and has therefore been proposed as a marker of 'true' autoimmune hepatitis type 2. Altogether 100 LKM1 positive sera were tested by immunodiffusion (ID). Twenty five gave a precipitation line with human liver cytosol; 17 of the 25 also reacted with rat liver cytosol. Thirteen of the 25 sera were anti-HCV positive by second generation ELISA: anti-HCV positive patients were significantly older (p LKM1, and that it is an additional marker of juvenile autoimmune hepatitis type 2. It does not, however, discriminate between patients with and without HCV infection. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7797126

Methionine metabolism after portacaval shunt in the rat

International Nuclear Information System (INIS)

Benjamin, L.E.; Steele, R.D.

1985-01-01

The effect of portacaval shunt (PCS) on methionine metabolism in the rat was investigated. Male Sprague-Dawley rats were subjected to PCS and maintained on an 18% casein diet. Growth curves of operated rats were similar to controls. PCS rats excreted more urinary 35 SO 4 and less [ 35 S]taurine than controls after intraperitoneal injection of 0.3 mmol/100 g [ 35 S]methionine or [ 35 S]cysteine. Total urinary taurine excretion was similar in PCS and control rats after a methionine or cysteine load; however, under basal conditions PCS rats had higher urinary taurine levels than controls, indicating that PCS may cause the taurine pool to be expanded. Hepatic methionine, S-adenosylmethionine, and cysteine pools were significantly decreased in PCS rats, while S-adenosylhomocysteine levels were unchanged. Relative rates of transsulfuration in PCS and control rats were studied by following the decrease in the 3 H-to- 35 S ratio in liver protein after injection of [methyl-3H]methionine and [ 35 S]methionine, and no difference in flux of 35 S from [ 35 S]methionine to [ 35 S]cysteine was found. Similarly, total hepatic activities of methionine adenosyltransferase, cystathionine synthase, and cystathionine gamma-lyase were unchanged in PCS rats. These results indicate that altered methionine metabolism in PCS rats is not explained by changes in conversion of methionine to cysteine via the transsulfuration pathway

Modulation of serum concentrations and hepatic metabolism of 17{beta}-estradiol and testosterone by amitraz in rats

Energy Technology Data Exchange (ETDEWEB)

Chou, Chen-Ping [National Taiwan University, Institute of Toxicology, College of Medicine, Taipei (China); Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Taichung (China); Lu, Shui-Yuan [Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Taichung (China); Ueng, Tzuu-Huei [National Taiwan University, Institute of Toxicology, College of Medicine, Taipei (China)

2008-10-15

The present study has investigated the ability of amitraz, a widely used formamidine pesticide, to modulate serum concentrations and liver microsomal metabolism of 17{beta}-estradiol (E2) and testosterone in rats. Amitraz was administered intraperitoneally to male rats for 4 days and to intact female rats or ovariectomized (OVX) and 0.5 mg/kg E2-supplemented female rats for 7 days. E2 and metabolites were analyzed by gas chromatography-electron capture detection and testosterone and metabolites were analyzed by high-pressure liquid chromatography. In OVX and E2-supplemented females, 50 mg/kg amitraz caused an 85% decrease of serum E2 concentration and a marked increase of 2-OH-E2 concentration. Amitraz at 25 and 50 mg/kg produced 9.0-fold or greater increases of serum testosterone and 2{beta}-OH-testosterone levels in males. Amitraz at 25 mg/kg resulted in no or minimal increases of liver microsomal formation of E2 or testosterone metabolites. Amitraz at 50 mg/kg produced 1.4- to 3.6-fold increases of 2-OH-E2; estrone; 2{beta}-, 6{beta}-, and 16{alpha}-OH-testosterone; and androstenedione formation in males and intact females. Amitraz at 50 mg/kg preferentially increased intact female 16{beta}-OH-testosterone production by 8.6-fold. In OVX females, E2 supplement alone or cotreatment with E2 and 50 mg/kg amitraz produced 1.3- to several-fold increases of 2- and 4-OH-E2 formation and 2{beta}- and 16{alpha}-OH-testosterone production. The cotreatment increased 6{beta}- and 16{beta}-OH-testosterone formation by 1.8- and 1.6-fold, respectively. The present findings show that amitraz induces hepatic E2 and testosterone metabolism in male and female rats, decreases serum E2 concentration in OVX and E2-supplemented females, but increases serum testosterone in males. (orig.)

Effects of red pitaya juice supplementation on cardiovascular and hepatic changes in high-carbohydrate, high-fat diet-induced metabolic syndrome rats.

Science.gov (United States)

Ramli, Nurul Shazini; Brown, Lindsay; Ismail, Patimah; Rahmat, Asmah

2014-06-12

The fruit of Hylocereus polyrhizus, also known as red pitaya, and buah naga in Malay, is one of the tropical fruits of the cactus family, Cactaceae. Red pitaya has been shown to protect aorta from oxidative damage and improve lipid profiles in hypercholesterolemic rats probably due to phytochemicals content including phenolics and flavonoids. The aim of this study was to investigate the changes in cardiac stiffness, hepatic and renal function in high-carbohydrate, high-fat diet-induced obese rats following supplementation of red pitaya juice. Total 48 male Wistar rats were divided into 4 groups: corn-starch group (CS), corn-starch+red pitaya juice group (CRP), high-carbohydrate, high fat group (HCHF) and high-carbohydrate, high fat+red pitaya juice (HRP). The intervention with 5% red pitaya juice was started for 8 weeks after 8 weeks initiation of the diet. Heart function was determined ex vivo with Langendorff hearts while plasma liver enzymes, uric acid and urea were measured using commercial kits. Total fat mass was determined with Dual-energy X-ray absorptiometry (DXA) scan. Glucose uptake was measured with Oral Glucose Tolerance Test (OGTT). Liver and cardiac structures were defined by histology. Supplementation of red pitaya juice for 8 weeks increased energy intake and abdominal circumference but no change in body fat and lean mass respectively. Also, there were a trend of uric acid and glucose normalization for HRP as compared to H-fed rats. Red pitaya juice treatment reduced ALP and ALT but caused significant increment in AST. Diastolic stiffness of the heart was reduced after supplementation of red pitaya juice in corn starch fed rats. However, the reduction was not significant in HRP rats in comparison with H rats. The present study concluded that red pitaya juice may serve as a complimentary therapy for attenuating some signs of metabolic syndrome.

Dietary fish oil stimulates hepatic low density lipoprotein transport in the rat.

Science.gov (United States)

Ventura, M A; Woollett, L A; Spady, D K

1989-01-01

These studies were undertaken to examine the effect of fish oil, safflower oil, and hydrogenated coconut oil on the major processes that determine the concentration of low density lipoprotein (LDL) in plasma, i.e., the rate of LDL production and the rates of receptor-dependent and receptor-independent LDL uptake in the various organs of the body. When fed at the 20% level, fish oil reduced plasma LDL-cholesterol levels by 38% primarily by increasing LDL receptor activity in the liver. Dietary safflower oil also increased hepatic LDL receptor activity; however, since the rate of LDL production also increased, plasma LDL-cholesterol levels remained essentially unchanged. Hydrogenated coconut oil had no effect on LDL receptor activity but increased the rate of LDL-cholesterol production causing plasma LDL-cholesterol levels to increase 46%. Dietary fish oil had no effect on the receptor-dependent transport of asialofetuin by the liver, suggesting that the effect of fish oil on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physical properties of hepatic membranes. Finally, dietary fish oil increased hepatic cholesteryl ester levels and suppressed hepatic cholesterol synthesis rates, suggesting that the up-regulation of hepatic LDL receptor activity in these animals was not simply a response to diminished cholesterol availability in the liver. PMID:2760200

Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease.

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Munoz-Garrido, Patricia; Marin, José J G; Perugorria, María J; Urribarri, Aura D; Erice, Oihane; Sáez, Elena; Úriz, Miriam; Sarvide, Sarai; Portu, Ainhoa; Concepcion, Axel R; Romero, Marta R; Monte, María J; Santos-Laso, Álvaro; Hijona, Elizabeth; Jimenez-Agüero, Raúl; Marzioni, Marco; Beuers, Ulrich; Masyuk, Tatyana V; LaRusso, Nicholas F; Prieto, Jesús; Bujanda, Luis; Drenth, Joost P H; Banales, Jesús M

2015-10-01

Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca(2+)]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated. Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS. Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA. UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients. Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

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.

Effects of a combined intervention with a lentil protein hydrolysate and a mixed training protocol on the lipid metabolism and hepatic markers of NAFLD in Zucker rats.

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Martínez, Rosario; Kapravelou, Garyfallia; Donaire, Ana; Lopez-Chaves, Carlos; Arrebola, Francisco; Galisteo, Milagros; Cantarero, Samuel; Aranda, Pilar; Porres, Jesus M; López-Jurado, María

2018-02-21

Metabolic syndrome is a cluster of metabolic alterations characterized by central obesity, dyslipidemia, elevated plasma glucose, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). In this study, a combined intervention of a lentil protein hydrolysate and a mixed training protocol was assessed in an animal experimental model of genetic obesity and metabolic syndrome. Thirty-two male obese and 32 lean Zucker rats were divided into eight different experimental groups. Rats performed a mixed exercise protocol or had a sedentary lifestyle and were administered a lentil protein hydrolysate or placebo. Daily food intake, weekly body weight gain, plasma parameters of glucose and lipid metabolisms, body composition, hepatic weight, total fat content and fatty acid profile, as well as gene expression of lipogenic and lipolytic nuclear transcription factors and their target genes were measured. Obese Zucker rats exhibited higher body and liver weight and fat content than did their lean counterparts. Such alterations were related to modifications in aerobic capacity, plasma biochemical parameters of glucose and lipid metabolisms, hepatic fatty acid profile and gene expression of nuclear transcription factors SREBP1c, PPARα, LXR and associated lipogenic and lipolytic enzymes. The interventions tested did not affect body weight gain but improved aerobic capacity, reduced hepatomegalia and steatosis associated with NAFLD and relieved the adverse effects produced by this condition in glucose and lipid metabolisms through the modulation in the expression of different genes involved in diverse metabolic pathways.

Grapefruit juice intake does not enhance but rather protects against aflatoxin B1-induced liver DNA damage through a reduction in hepatic CYP3A activity.

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Miyata, Masaaki; Takano, Hiroki; Guo, Lian Q; Nagata, Kiyoshi; Yamazoe, Yasushi

2004-02-01

Influence of grapefruit juice intake on aflatoxin B1 (AFB1)-induced liver DNA damage was examined using a Comet assay in F344 rats given 5 mg/kg AFB1 by gavage. Rats allowed free access to grapefruit juice for 5 days prior to AFB1 administration resulted in clearly reduced DNA damage in liver, to 65% of the level in rats that did not receive grapefruit juice. Furthermore, rats treated with grapefruit juice extract (100 mg/kg per os) for 5 days prior to AFB1 treatment also reduced the DNA damage to 74% of the level in rats that did not receive grapefruit juice. No significant differences in the portal blood and liver concentrations of AFB1 were observed between grapefruit juice intake rats and the controls. In an Ames assay with AFB1 using Salmonella typhimurium TA98, lower numbers of revertant colonies were detected with hepatic microsomes prepared from rats administered grapefruit juice, compared with those from control rats. Microsomal testosterone 6beta-hydroxylation was also lower with rats given grapefruit juice than with control rats. Immunoblot analyses showed a significant decrease in hepatic CYP3A content, but not CYP1A and CYP2C content, in microsomes of grapefruit juice-treated rats than in non-treated rats. No significant difference in hepatic glutathione S-transferase (GST) activity and glutathione content was observed in the two groups. GSTA5 protein was not detected in hepatic cytosol of the two groups. In microsomal systems, grapefruit juice extract inhibited AFB1-induced mutagenesis in the presence of a microsomal activation system from livers of humans as well as rats. These results suggest that grapefruit juice intake suppresses AFB1-induced liver DNA damage through inactivation of the metabolic activation potency for AFB1 in rat liver.

Starvation and refeeding in rats: effect on some parameters of energy metabolism and electrolytes and changes of hepatic tissue

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Fatemeh Namazi

Full Text Available Abstract: Regarding the importance of starvation and refeeding and the occurrence of refeeding syndrome in various conditions, the present study was conducted to investigate the effects of refeeding on some parameters of energy metabolism and electrolytes and changes of hepatic tissue in male Wistar rats. Fifty-seven rats were divided into six groups, having 6 to 11 rats. Food was provided ad-libitum until three months and then the first group was considered without starvation (day 0. Other rats were fasted for two weeks. Group 2 was applied to a group immediately after starvation (day 14. Groups 3 to 6 were refed in days 16 till 22, respectively. At the end of each period, blood and tissue samples were taken and histopathological and serum analysis, including serum electrolytes (calcium, phosphorus, sodium, potassium, the energy parameters (glucose, insulin, cortisol and the liver enzymes (ALT, AST, ALP were determined. Insulin decreased by starvation and then showed an increasing trend compared to starvation period, which the highest amount of this parameter was observed eight days post-refeeding. Serum glucose level showed the opposite pattern of insulin. Histopathological examination of the tissue sections revealed clear vacuoles after starvation and refeeding, in which the severity of lesions gradually decreased during refeeding. The cortisol level decreased by starvation and then increased during refeeding. Also, potassium and phosphorus concentrations declined by refeeding and the serum sodium and potassium levels were changed in the relatively opposite manner. The calcium level decreased by starvation and then increased during refeeding. These results could help recognize and remedy the refeeding syndrome.

A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats

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Hongjun Xiang

2017-03-01

Full Text Available A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11, 12-dien-28-oic acid (Oxy-Di-OA, has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV (Hepatitis B Virus activity (IC50 = 3.13 µg/mL. Remarkably, it is superior to lamivudine in the inhibition of the rebound of the viral replication rate. Furthermore, Oxy-Di-OA showed good performance of anti-HBV activity in vivo. Some studies showed that liver fibrosis may affiliate with HBV gene mutations. In addition, the anti-hepatic fibrosis activity of Oxy-Di-OA has not been studied. Therefore, we evaluated the protective effect of Oxy-Di-OA against carbon tetrachloride (CCl4-induced liver injury in rats. Daily intraperitoneally administration of Oxy-Di-OA prevented the development of CCl4-induced liver fibrosis, which was evidenced by histological study and immunohistochemical analysis. The entire experimental protocol lasted nine weeks. Oxy-Di-OA significantly suppressed the increases of plasma aspartate aminotransferase (AST and alanine aminotransferase (ALT levels (p < 0.05. Furthermore, Oxy-Di-OA could prevent expression of transforming growth factor β1 (TGF-β1. It is worth noting that the high-dose group Oxy-Di-OA is superior to bifendate in elevating hepatic function. Compared to the model group, Oxy-Di-OA in the high-dose group and low-dose group can significantly reduce the liver and spleen indices (p < 0.05. The acute toxicity test showed that LD50 and a 95% confidence interval (CIs value of Oxy-Di-OA were 714.83 mg/kg and 639.73–798.73 mg/kg via intraperitoneal injection in mice, respectively. The LD50 value of Oxy-Di-OA exceeded 2000 mg/kg via gavage in mice. In addition, a simple and rapid high performance liquid chromatography-ultraviolet (HPLC-UV method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of Oxy-Di-OA (Cmax

Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.

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Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu

2014-03-15

High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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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.

Maternal resveratrol intake during lactation attenuates hepatic triglyceride and fatty acid synthesis in adult male rat offspring

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Masato Tanaka

2017-03-01

Full Text Available Resveratrol (3,5,4-trihydroxystilbene is a natural polyphenolic compound found in grapes and red wine and has been shown to exert protective effects on the liver preventing lipid accumulation induced by a high-fat diet. However, no studies have shown that the nutritional resveratrol intake by the parental generation has modified lipogenesis in an adult offspring. The aim of this study was to investigate whether maternal resveratrol intake during lactation affects lipogenesis in adult male rat offspring, and if it does, what is the molecular mechanistic basis. Six male pups born from mothers given a control diets during lactation (CC group and six male pups born from mothers given a control diet as well as resveratrol during lactation (CR group were fed a standard diet until sacrifice at 36 weeks. Adult male offspring from mothers given resveratrol during lactation (CR group had lower body weight from the fourth week of lactation until adulthood, but no significant change was observed in the relative food intake. Low levels of plasma triacylglycerol were found in the CR group compared to the CC group. Histopathological analysis of the livers of adult male rat offspring revealed lipid accumulation in hepatocytes in the CC group, whereas lipid droplets were rare in the CR group. Hepatic protein levels of AMPK-phosphorylated at ser403, Sirt1, and Nampt in the CR group were upregulated significantly compared to the CC group. These results indicated the maternal resveratrol intake during lactation-induced activation of AMPK through Sirt1 upregulation. In this study, significant upregulation of the levels of precursor of sterol regulatory element binding protein-1c (SREBP-1c and downregulation of the ratio of active-SREBP-1c/precusor-SREBP-1c were observed in the CR group compared to the CC group. These results suggested that proteolytic processing of SREBP-1c was suppressed by AMPK in the livers of the CR group. It is well known that SREBP-1c

In vivo determination of triglyceride (TG) secretion in rats fed different dietary saturated fats using [2-3H]-glycerol

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Lai, H.C.; Yang, H.; Lasekan, J.; Clayton, M.; Ney, D.M.

1990-01-01

Male, Sprague-Dawley rats (154±1 g) were fed diets containing 2% corn oil (CO) + 14% butterfat (BF), beef tallow (BT), olive oil (OO) or coconut oil (CN) vs a 16% CO control diet for 5 weeks. Changes in plasma TG specific activity (dpm/mg TG) were determined in individual unanesthetized rats after injection of 100 μCi [2- 3 H]-glycerol via a carotid cannula. Fractional rate constants were obtained using a 2-compartment model and nonlinear regression analysis. Results demonstrated no difference in the fractional rate constants among dietary groups; but, differences in the rates of hepatic TG secretion were noted. Rats fed BT showed a higher rate of hepatic TG secretion than rats fed CO. Rats fed BF, OO or CN showed somewhat higher rates of hepatic TG secretion than CO. VLDL TG, phospholipid, and apolipoprotein B and E levels were higher with saturated fats vs CO. The data suggest that the higher plasma TG levels noted in response to feeding saturated fats vs corn oil can be explained, in part, by an increased flux of hepatic TG secretion

Influence of Piper betle on hepatic marker enzymes and tissue antioxidant status in D-galactosamine-induced hepatotoxic rats.

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Pushpavalli, Ganesan; Veeramani, Chinnadurai; Pugalendi, Kodukkur Viswanathan

2008-01-01

D-galactosamine is a well-established hepatotoxicant that induces a diffuse type of liver injury closely resembling human viral hepatitis. D-galactosamine by its property of generating free radicals causes severe damage to the membrane and affects almost all organs of the human body. The leaves of Piper betle L., a commonly used masticatory in Asian countries, possess several biological properties. Our aim is to investigate the in vivo antioxidant potential of P. betle leaf-extract against oxidative stress induced by D-galactosamine intoxication in male albino Wistar rats. Toxicity was induced by an intraperitoneal injection of D-galactosamine, 400 mg/kg body weight (BW) for 21 days. Rats were treated with P. betle extract (200 mg/kg BW) via intragastric intubations. We assessed the activities of liver marker enzymes (aspartate amino-transferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase) and levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides, superoxide dismutase, catalase, glutathione peroxidase, vitamin C, vitamin E, and reduced glutathione. The extract significantly improved the status of antioxidants and decreased TBARS, hydroperoxides, and liver marker enzymes when compared with the D-galactosamine treated group, demonstrating its hepatoprotective and antioxidant properties.