Co-administration of cyclosporine an alleviates thioacetamide-induced liver injury

AIM: To investigate the effects of cyclosporine A (CsA) on thioacetamide (TAA)-induced liver injury.METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group showsh igher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4) in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section,TGFβ-R1 and FGFR4 are more concentrated in rat liverafter CsA plus TAA injury.CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.     

Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats

BACKGROUND/AIMS: Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS: Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS: Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS: In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.     

Murine model to study brain,behavior and immunity during hepatic encephalopathy

AIM:To propose an alternative model of hepatic encephalopathy(HE) in mice,resembling the human features of the disease.METHODS:Mice received two consecutive intraperitoneal injections of thioacetamide(TAA) at low dosage(300 mg/kg).Liver injury was assessed by serum transaminase levels(ALT) and liver histology(hematoxylin and eosin).Neutrophil infiltration was estimated by confocal liver intravital microscopy.Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time.Hemodynamic parameters were measured through tail cuff.Ammonia levels were quantified in serum and brain samples.Electroencephalography(EEG) and psychomotor activity score were performed to show brain function.Brain edema was evaluated using magnetic resonance imaging.RESULTS:Mice submitted to the TAA regime developed massive liver injury,as shown by elevation of serum ALT levels and a high degree of liver necrosis.An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury.This led to mice mortality and weight loss,which was associated with severe coagulopathy.Furthermore,TAA-treated mice presented with increased serum and cerebral levels of ammonia,in parallel with alterations in EEG spectrum and discrete brain edema,as shown by magnetic resonance imaging.In agreement with this,neuropsychomotor abnormalities ensued 36 h after TAA,fulfilling several HE features observed in humans.In this context of liver injury and neurological dysfunction,we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome.CONCLUSION:In summary,we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans,which may provide new insights for treatment.     

硫代乙酰胺诱导的急性肝损伤大鼠肝组织Norrin/Frizzled-4表达的变化*

目的 建立硫代乙酰胺（TAA）诱导的大鼠急性肝损伤模型,探讨Norrin/Frizzled-4在肝损伤间质重建中的作用。 方法 随机将32只SD大鼠分为正常对照组（N组）8只和TAA诱导组（M组）24只。建立TAA诱导的肝损伤大鼠模型。采用ELISA法检测血清CD105和血管内皮细胞生长因子（VEGF）水平,采用Western blot法检测原代肝星状细胞和肝组织Norrin/Frizzled-4信号通路中细胞外配体蛋白Norrin和细胞膜特异性受体蛋白Frizzled-4的表达。 结果 24只TAA诱导组大鼠死亡11只（45.8%）;病理学检查显示急性肝损伤大鼠模型建立成功;对照组血清CD105水平为（2.18±0.05） ng/mL,显著低于TAA处理1 w组的（2.36±0.07） ng/mL或2 w组的（2.42±0.03） ng/mL,差异均有显著性（P<0.05）;对照组血清VEGF为（61.48±0.39） pg/mL,显著低于模型组的（64.52±0.25） pg/mL,差异均有显著性（P<0.01）;原代肝星状细胞和正常肝组织不表达Norrin蛋白或Frizzled-4蛋白,或表达量很低,急性肝损伤大鼠肝组织Norrin/Frizzled-4表达显著高于正常对照组,差异均有显著性（P<0.01）。 结论 急性肝损伤大鼠肝组织Norrin/Frizzled-4蛋白表达上调,可能与急性肝损伤初期维持血管网络形态及肝间质重建有关。     

Down-regulation of TGFbeta1 and leptin ameliorates thioacetamide-induced liver injury in lipopolysaccharide-primed rats

Pretreatment with a low dose of bacterial endotoxin (lipopolysaccharide, LPS) caused the reduction of cytochrome P450 (CYP) enzymes and inflammatory factors which are capable of protecting the liver from a lethal LPS challenge. However, the effects of LPS pretreatment on the expression of transforming growth factor beta1 (TGFbeta1) and leptin in thioacetamide (TAA)-induced liver fibrosis remain unknown. In this study, Sprague-Dawley rats were pretreated intraperitoneally with LPS (5 mg/kg body weight) for 24 h, and subsequently treated with TAA (200 mg/kg body weight/ 3 days) for 1 month to examine the effects of LPS on TAA-injured rats. LPS pretreatment was associated with lower granulation and lower (P < 0.05) GOT/GPT than in TAA-injured rats. The LPS-pretreated group had less collagen (Sirius red histochemical staining). Semiquantitative RT-PCR showed that the levels of collagen 3 and TGFbeta1 mRNAs were lower (P < 0.05) in the liver of LPS-pretreated rats than in TAA-injured rats. TGFbetaRI mRNA in the liver of LPS-pretreated rats exceeded (P < 0.05) that in TAA-injured rats. LPS pretreatment reduced the leptin content (Western blot) below that of TAA-injured rats. These results imply that LPS pretreatment (endotoxin tolerance) alleviates the TAA-induced liver fibrosis of rats by reducing TGFbeta1 and leptin content.     

Expression patterns of cell cycle-related proteins in a rat cirrhotic model induced by CCl4 or thioacetamide

To analyze the aberrant expression of cell cycle-related proteins and their biological significance in relation to cirrhosis, we compared the cirrhotic patterns induced by two different types of cirrhotic agents, CCl₄ and thioacetamide (TAA) in rats. CCl₄ or TAA treatment was given to rats for 8 or 30 weeks, respectively, and the livers were removed at 9, 20, and 30 weeks after the experiment began. The TAA-induced fibrotic pattern was different from the CCl₄-induced one, in terms of the formation of fibrous connective tissue and the proliferation of bile ductule cells. Cholangiofibrosis and clear cell foci were also observed in TAA-treated rats at 30 weeks. Histological examination revealed severe cirrhotic changes at 9 weeks in CCl₄-treated rats and at 30 weeks in TAA-treated rats. Immunoblotting for cyclin D1, E, A, B, and proliferating cell nuclear antigen (PCNA) and their counterpart protein kinases (CDK2, 4, and CDC2) showed significant overexpression in rats with severely cirrhotic livers. The p53 tumor suppressor protein increased dramatically in the CCl₄-treated group, while it was not detected in the livers of TAA-treated rats. Upregulation of p21^WAF1, a CDK inhibitory protein, was detected in TAA-treated rats, but not in CCl₄-treated rats. Immunohistochemical data for cyclin D1, E, and PCNA were well correlated with immunoblotting data; these proteins were increased in hepatocytes surrounding the cirrhotic lesions, suggesting that hepatocyte regeneration is correlated with cell cycle-related protein expression in cirrhotic liver. In the TAA-treated rats, the expression of these proteins was increased both in hepatocytes and in ductule cells. Our data suggest that liver cirrhosis induced by CCl₄ or TAA is associated with alterations in cell cycle-related proteins, and that the expression of these proteins is responsible for hepatocyte regeneration in the damaged liver and may be involved in liver carcinogenesis. Received: May 1, 2000 / Accepted: August 25, 2000     

Simvastatin for rats with thioacetamide-induced liver failure and encephalopathy

Background and Aim:  Nitric oxide (NO) inhibition aggravates hepatic damage and encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure. Statins enhance NO synthase expression beyond their lipid-lowering capability, but the impact on encephalopathy remains unexplored. The aim of this study was to assess the effects of simvastatin on rats with TAA-induced acute liver damage and hepatic encephalopathy.
Methods:  Sprague–Dawley rats received TAA (350 mg/kg/day) or normal saline (NS) by intraperitoneal injection for 3 consecutive days. Two days before injections, each group was divided into three subgroups, taking (i) distilled water; (ii) simvastatin (20 mg/kg/day); or (iii) simvastatin plus N ^G-nitro- l -arginine methyl ester (L-NAME, 25 mg/kg/day) by oral gavage for 5 days. On the fifth day, severity of encephalopathy was assessed and plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and ammonia were measured.
Results:  The TAA subgroups showed higher ALT, AST, bilirubin and ammonia levels and lower motor activity counts as compared with the NS subgroups. Among the TAA-treated subgroups, rats with simvastatin treatment exerted higher motor activity counts and survival rate ( P  = 0.043), and a trend of lower ALT, AST, bilirubin and ammonia levels than those receiving saline. All rats that underwent simvastatin plus L-NAME treatment died during or after TAA injections.
Conclusions:  Simvastatin improved encephalopathy and survival in TAA-administered rats. The beneficial effect was offset by L-NAME, suggesting the role of NO in liver damage and encephalopathy.     

钉螺转氨酶的初步研究

纸层析法证明丙氨酸、天门冬氨酸及精氨酸经过钉螺匀浆作用后可使α-酮戊二酸转变成谷氨酸,说明钉螺存在谷-丙、谷-草及谷-精转氨酶。比色法也测得谷-草转氨酶和谷-丙转氨酶的活力。溴乙酰胺对上述两酶活力无明显影响,而烟酰苯胺有抑制钉螺谷-丙转氨酶作用。小剂量溴乙酰胺与烟酰苯胺盐酸盐伍用,无增强杀螺作用。     

Chronic permanent hypoxemia predisposes to mild elevation of liver stiffness

AIM:To evaluate the impact of long term permanent hypoxemia noticed in patients with non operated congenital cyanogenic cyanotic cardiopathy on liver stiffness.METHODS:We included ten adult patients with non operated inoperate cyanotic cardiopathy and ten matched patients for age and gender admitted to the gastroenterology department for proctologic diseases;Clinical and laboratory data were collected[age,gender,body mass index,oxygen saturation,glutamate oxaloacetate transaminase(GOT),glutamate pyruvate transaminase(GPT),glycemia and cholesterol].Measurement of hepatic stiffness by transient elastography was carried out in all patients using the Fibroscan device.All patients underwent an echocardiography to eliminate congestive heart failure.RESULTS:Among the patients with cyanotic cardiopathy,median liver stiffness 5.9±1.3 kPa was greater than control group(4.7±0.4 kPa)(P=0.008).Median levels of GOT,GPT,gamma-glutamyltransferase,glycemia and cholesterol were comparable in cardiopathy and control group.In regression analysis including age,gender,body mass index,oxygen saturation,GOT,GPT,glycemia,cholesterol showed that only oxygen saturation was related to liver stiffness(r=-0.63 P=0.002).CONCLUSION:Chronic permanent hypoxemia can induce mild increase of liver stiffness,but further studies are needed to explore the histological aspects of liver injury induced by chronic permanent hypoxemia.     

Age-dependent phagocytosis of erythrocytes by the isolated perfused rat liver after galactosamine hepatitis and alpha-naphthylisothiocyanate cholestasis

Isolated rat livers were perfused with an immunoglobulin-free fluid containing homologous rat erythrocytes suspended in an isotonic saline solution. Galactosamine hepatitis and alpha-naphthylisothiocyanate cholestasis were induced as experimental liver diseases. The glutamic oxalacetic transaminase (GOT) and guanosine triphosphate (GPT) activities, the potassium level as well as the redox quotients of lactate/pyruvate and beta-hydroxybutyrate/acetoacetate were determined as liver function parameters. Results: The same dose of galactosamine led to two different types of reaction. The group suffering more damage (rendering maximum GOT activities) phagocytosed significantly (p less than or equal to 0.05) more erythrocytes than the other group. Galactosamine hepatitis significantly slows down the phagocytosis of erythrocytes. The function of the mononuclear phagocytosing cells in the liver is intact. The alpha-naphthylisothiocyanate (ANIT) cholestasis significantly reduces the capacity of the mononuclear phagocytosing cells in the liver. Young erythrocytes were phagocytosed significantly better than old ones in either type of liver damage, in galactosamine hepatitis and in ANIT cholestasis as well as by healthy livers.     

急性肝损伤大鼠肠源性内毒素血症形成机理及其作用的实验研究

探讨急性肝损伤大鼠肠源性内毒素血症的形成机理及肠源性内毒素血症在急性肝损伤过程中的作用.采用皮下注射硫代乙酰胺（TAA）600 mg/kg制作大鼠急性肝损伤动物模型,取回肠内容物、肝、脾、淋巴结作细菌培养,检测血浆及回肠内容物内毒素含量.行血浆D-乳酸的检测.取肝脏和回肠作病理切片.结果显示TAA诱导大鼠急性肝损伤后,血浆及回肠内容物内毒素水平上升明显（P＜0.01）,血浆TNF-α含量升高明显（P＜0.01）,且与内毒素水平升高呈正相关（P＜0.01）.同时出现肠道菌群失调,肠道通透性增加,肠道细菌移位.回肠病理所示肠绒毛明显变短、破坏、炎性细胞浸润增多.因此肠道菌群失调、肠粘膜结构改变、肠道通透性增加及肠道细菌移位是形成肠源性内毒素血症的重要因素.内毒素可直接或通过诱导TNF-α加重肝损伤.     

Effects of aspirin and enoxaparin in a rat model of liver fibrosis

AIM To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis.METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group(n = 5) and model group(n = 40). Thioacetamide(TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously(n = 9), TAA + low-dose aspirin(n = 9), TAA + high-dose aspirin(n = 9) or TAA + enoxaparin(n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. RESULTS Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed.CONCLUSION Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.     

Hepatic stimulator substance activity in the liver of thioacetamide-intoxicated rats

AIMS/BACKGROUND: Hepatic stimulator substance (HSS) is a known hepatic growth factor which appears to be organ-specific but species non-specific. We have recently shown that the administration of HSS enhanced hepatocyte proliferation occurring due to thioacetamide (TAA)-induced liver injury in rats (Theocharis SE, et al., Scand J Gastroenterol 1998; 33: 656-63). In the present study, we examined the activity of the endogenously produced HSS in the liver of TAA administered rats during injury and regeneration. METHODS: TAA at a dose of 300 mg/kg of body weight was injected intraperitoneally in male Wistar rats. The animals were sacrificed at 0, 12, 24, 36, 48, 60 and 72 h after TAA administration. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase and the assessment of mitotic index in hepatocytes were used to estimate liver regeneration. HSS extract was obtained from the livers of TAA-treated rats, sacrificed at the above mentioned time points. This HSS extract was injected in 34% partially hepatectomized rats, to assess its activity. The ability of the injected HSS extract to increase hepatocellular proliferation over that normally occurring 24 h following 34% partial hepatectomy was used to express the activity of HSS by determining the above mentioned indices of liver regeneration. RESULTS: The administration of TAA caused severe hepatic injury recognized histopathologically as well as by the increased activities of serum hepatic enzymes aspartate and alanine aminotrasferases. The hepatic injury, which peaked at 24 and 36 h post-TAA treatment (p<0.001), was followed by hepatocyte proliferation, presenting peaks at 48 and 60 h (p<0.001). The activity of the endogenously produced HSS from livers of TAA-treated rats increased at 36 h after TAA administration as well as being highly expressed at 48 and 60 h thus coinciding with the peak of hepatocyte proliferation. At other time points, HSS activity was decreased. CONCLUSIONS: The observed variations of HSS activity in rat liver suggest active participation of this growth factor in hepatocyte replication which follows toxin-induced liver injury as a repair mechanism process.     

Leptin administration exacerbates thioacetamide-induced liver fibrosis in mice

AIM: To investigate the effects of leptin administration on liver fibrosis induced by thioacetamide (TAA). METHODS: Twenty-four male C57Bl/6 mice were randomly allocated into four groups, which were intra-peritoneally given saline (2 mL/kg), leptin (1 mg/kg), TAA (200 mg/kg), TAA (200 mg/kg) plus leptin (1 mg/kg) respectively, thrice a week. All mice were killed after 4 wk. The changes in biochemical markers, such as the levels of alanine aminot-ransferase (ALT) and aspartate aminotransferase (AST) in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver were determined. For histological analysis, liver tissues were fixed with 10% buffered formalin, embedded with paraffin. Hematoxylin-eosin (HE) staining and picric acid-Sirius red dyeing were performed. The level of α1(I) procollagen mRNA in liver tissues was analyzed by RT-PCR. RESULTS: Apparent liver fibrosis was found in TAA group and TAA plus leptin group. Compared to saline group, the levels of ALT and AST in serum and MDA in liver increased in TAA group (205.67±27.69 U/L vs50.67±10.46 U/L, 177.50±23.65 U/L vs 76.33±12.27 U/L, 2.60±0.18 nmol/mg pro vs 1.91±0.14 nmol/mg pro, P<0.01) and in TAA plus leptin group (256.17±22.50 U/L vs 50.67±10.46 U/L, 234.17±27.37 U/L vs 76.33±12.27 U/L, 2.97±0.19 nmol/mg pro vs 1.91±0.14 nmol/mg pro,P<0.01). The level of SOD in livers decreased (51.80±8.36 U/mg pro vs 81.52±11.40 U/mg pro, 35.78±6.11 U/mg pro vs 81.52± 11.40 U/mg pro, P<0.01) and the level of α1(I) procollagen mRNA in liver tissues also increased (0.28±0.04 vs 0.11± 0.02, 0.54±0.07 vs 0.11±0.02, P<0.01). But no significant changes were found in leptin group and saline group. Compared to TAA group, ALT, AST, MDA, and α1(I) procollagen mRNA and grade of liver fibrosis in TAA plus leptin group increased (256.17±22.50 U/L vs 205.67± 27.69 U/L, P<0.05; 234.17±27.37 U/L vs 177.50±23.65 U/L, P<0.05; 2.97±0.19 nmol/mg pro vs 2.60±0.18 nmol/mg pro,P<0.05; 0.54±0.07 vs 0.28±0.04, P<0.01; 3.17 vs 2.00, P<0.05), and the level of SOD in liver decreased (35.78±6.11 U/mg pro vs 51.80±8.36 U/mg pro, P<0.05). There were similar changes in the degree of type I collagen deposition confirmed by picric acid-Sirius red dyeing. CONCLUSION: Leptin can exacerbate the degree of TAA-induced liver fibrosis in mice. Leptin may be an important factor in the development of liver fibrosis.     

Curcumin ameliorates acute thioacetamide-induced hepatotoxicity

BACKGROUND AND AIM: Increased production of reactive oxygen species and nitric oxide and activation of nuclear factor kappa B are implicated in the pathogenesis of various liver diseases, including fulminant hepatic failure. Curcumin is a naturally occurring anti-oxidant that reduces oxidative stress and inhibits nuclear factor kappa B and nitric oxide formation. The aim of the present study is to assess curcumin's therapeutic potential in acute thioacetamide hepatotoxicity, a rat model of fulminant hepatic failure. METHODS: Fulminant hepatic failure was induced by two intraperitoneal (i.p.) injections of 300 mg/kg thioacetamide (TAA) at 24-h intervals. The experimental groups received a low-dose (200 mg/kg per day, i.p.) or a high-dose (400 mg/kg per day) of curcumin, initiated 48 h prior to the first TAA injection. A fourth group was administered neither TAA nor curcumin and served as a control. RESULTS: The survival rate was higher in both curcumin-treated groups compared to the TAA only treated group. Biochemical parameters of liver injury, blood ammonia and hepatic necroinflammation were lower in the low-dose curcumin group compared to TAA controls, and were further reduced in the high-dose group (P < 0.05 and P < 0.01, respectively). Curcumin treatment also reduced the TAA-induced elevated hepatic levels of thiobarbituric acid-reactive substances (TBARS), and inhibited the nuclear binding of nuclear factor kappa B (NFkappaB) and inducible nitric oxide (iNOS) protein expression. CONCLUSIONS: Curcumin improved survival and minimized oxidative stress, hepatocellular injury and hepatic necroinflammation, NFkappaB binding and iNOS expression in a rat model of FHF. These findings support the role of ROS, NFkappaB and iNOS in mediating liver insult due to TAA, and that of curcumin as a hepato-protectant.     

Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats

AIM:To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentallyinduced hepatic cirrhosis in rats.METHODS:Liver cirrhosis was induced by injections of thioacetamide(TAA).Rats were treated concurrently with TAA alone or TAA and either atorvastatin(1,10 and 20 mg/kg) or rosuvastatin(1,2.5,5,10 and 20 mg/kg) given daily by nasogastric gavage.RESULTS:Liver fibrosis and hepatic hydroxyproline content,in the TAA-treated group was significantly higher than those of the controls [11.5 ± 3.2 vs 2.6 ± 0.6 mg/g protein(P = 0.02)].There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins.Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension,and had no effect on hepatic oxidative stress.Accordingly,the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only.In vitro studies,using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation.Nevertheless,statin treatment was not associated with worsening of liver damage,portal hypertension or survival rate.CONCLUSION:Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats.Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation.     

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats

BACKGROUND AND AIMS: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. METHODS: Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. RESULT: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. CONCLUSION: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.     

Intermediary metabolism in a lizard, Calotes versicolor: role of thyroid hormones

In Calotes versicolor, thyroidectomy did not alter the blood glucose level, lactate dehydrogenase (LDH liver and heart), acid phosphatase (Ac.Pase liver and kidney), and alkaline phosphatase (Alk.Pase liver and kidney) activities; significantly decreased the activities of glucose-6-phosphatase (G-6-Pase liver and kidney), glutamic oxaloacetic transaminase (GOT liver and heart), glutamic pyruvic transaminase (GPT liver), and urea concentration (liver and kidney); and increased liver cholesterol when compared to sham-operated controls. Administration of L-thyroxine (L-T4) or triiodo-L-thyronine (L-T3) to thyroidectomized lizards significantly stimulated the activities of G-6-Pase, Ac.Pase, GOT and GPT, concentration of glucose and urea, and decreased the cholesterol level. While the activities of all the enzymes studied and cholesterol level remain unchanged, glucose and urea levels decreased and increased, respectively, in thyroidectomized animals treated with actinomycin D. Chloramphenicol treatment did not affect any of the parameters studied. Simultaneous injections of actinomycin D or chloramphenicol with L-T4 prevented the hormone-stimulated activities of Ac.Pase, GOT, and GPT while the activities of LDH, G-6-Pase, Alk.Pase, glucose, urea, and cholesterol levels remain unchanged.     

Radioimmunoassay estimates of plasma gonadotropin levels in the spawning pink salmon

The effects of cortisol and cortisone on liver glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities in two species of salmonids, the rainbow trout (Salmo gairdnerii) and the brook trout (Salvelinus fontinalis) were determined. Cortisol and cortisone increased liver GPT activity. Cortisone did not increase GOT activity and cortisol increased GOT activity only at high concentrations.Fish treated with cortisol lost nearly twice as much weight as did cortisonetreated and control fish. Cortisol was converted to cortisone in vivo, but cortisone was not converted measurably to cortisol. It is concluded that cortisone was biologically active in these salmonids.It is suggested that corticosteroids have an important part to play in the catabolism of protein for the provision of metabolic energy in these salmonids.