Effect of Glutathione Administration on Hepatic Biliary and Plasmatic Glutathione Levels in the Rat

Vendemiale G, Palmieri V, Palasciano G, Altomare E. Effect of glutathione administration on hepatic biliary and plasmatic glutathione levels in the rat. Scand J Gastroenterol 1994;29:1034-1038.

Background: Since the effect of exogenous glutathione (GSH) on overall hepatic GSH homeostasis is not known, the present study investigated the changes in the hepatic, biliary, and plasmatic GSH levels during GSH administration in intact rats

Methods: An exteriorized biliary-duodenal fistula was established, and GSH (1 mmol/kg over 2 h) or saline was administered intraperitoneally to rats with or without pretreatment with 5 mmol/kg L-serine borate, an inhibitor of gamma-glutamyltransferase (GGT).

Results: Three hours after GSH administration, biliary GSH efflux and bile flow rose from 104.7 ± 5.6 to 290.6 ± 8.6μg/ml bile and from 20.2 ± 1.3 to 30.2 ± 2.1 μl/min, respectively; GSH-treated rats also showed increased liver (35%) and posthepatic vein plasma (68%) GSH concentrations compared with controls. By contrast, in rats pretreated with the GGT inhibitor GSH administration appeared to be devoid of any effect, except for a modest biliary GSH increase.

Conclusions: This study indicates that significant changes occur in the hepatic GSH homeostasis after intraperitoneal GSH administration. The activity of hepatic GGT. most likely through degradation of circulating GSH, followed by an increase in cysteine availability, seems to account, at least partially, for the reported effects.     

Effects of salviainolic acid A (SA‐A) on liver injury: SA‐A action on hepatic peroxidation

Abstract: Background/Aims: This study aimed to investigate the actions of salviainolic acid A (SA‐A), an antiperoxidative component of Salvia miltiorrhiza (Sm), on rat liver injury and fibrosis. Methods: Acute and chronic rat liver injury models were established using carbon tetrachloride (CCl₄). After 48 h (acute) or during 6 weeks of CCl₄ injection, rats were further divided and treated with biphenyl dimethyl‐dicarboxylate (BDD) or colchicine, as a control antifibrotic treatment, with Sm, a herbal compound, or SA‐A, a water‐soluble extract of Sm. Liver function was investigated by assessing alanine transaminase (ALT) and aspartate transaminase (AST) activities, histological analysis, hydroxyproline (Hyp) and malondiadehyde (MDA) content. In vitro, isolated cultured hepatocytes were injured with CCl₄ gas for 24 h, followed by treatment with either vitamin E or various concentrations of SA‐A. The extent of hepatocyte injury was monitored by analyzing various lipid peroxidative parameters such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), lactase dehydrogenase (LDH), and glutathione peroxidase (GSH‐PX) levels in hepatocyte supernatants. Results: SA‐A significantly decreased abnormal serum ALT activity both in acutely and chronically injured rat livers, decreased abnormal serum AST activity, Hyp and MDA content and attenuated hepatic collagen deposition. After CCl₄ incubation and injury, the activities of AST, ALT CAT, GSH‐PX and LDH and MDA content in hepatocyte supernatants increased significantly, but GSH levels decreased significantly. SA‐A markedly improved these pathological changes in a dose‐dependent manner. 10^?4 mol/l SA‐A had stronger inhibitory action than vitamin E. Conclusions: Our studies suggest that SA‐A has antiperoxidative effects on injured hepatocytes in liver injury and fibrosis induced by CCl₄.     

Effect of melatonin on changes in hepatic antioxidant enzyme activities in rats treated with α-naphthylisothiocyanate

We have reported that melatonin protects against alpha-naphthylisothiocyanate (ANIT)-induced acute liver injury in rats by preventing enhanced lipid peroxidation. Herein, we examine the effect of melatonin on hepatic antioxidant enzyme activities in rats with a single i.p. injection of ANIT (75 mg/kg body weight) in order to clarify the protective mechanism of the indoleamine against ANIT-induced acute liver injury. Rats received a single oral administration of melatonin (10 or 100 mg/kg body weight) at 12 hr after ANIT treatment. Hepatic Cu,Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), and glucose-6-phosphate dehydrogenase (G-6-PDH) activities and reduced glutathione (GSH) concentration were determined 12 and 24 hr after ANIT treatment. ANIT-treated rats showed decreases in hepatic Cu,Zn-SOD and GSSG-R activities at 24 hr after treatment, transient increases in hepatic CAT and Se-GSH-Px activities at 12 hr, and no changes in hepatic Mn-SOD and G-6-PDH activities at 12 or 24 hr. Only the high dose of melatonin attenuated the decrease in hepatic Cu,Zn-SOD activity, while both doses of the indoleamine almost completely attenuated the decrease in hepatic GSSG-R activity. Neither dose of melatonin affected hepatic CAT, Se-GSH-Px, and G-6-PDH activities. ANIT-treated rats showed an increase in hepatic GSH concentration at 24 hr after treatment. Neither dose of melatonin affected the increase in hepatic GSH concentration. These results indicate that orally administered melatonin prevents decreases in Cu,Zn-SOD and GSSG-R activities in the liver of ANIT-treated rats, and suggest that the indoleamine may protect against ANIT-induced acute liver injury by attenuating the disruption of hepatic antioxidant defense systems.     

Sources of plasma glucose and liver glycogen in fasted ob/ob mice

Abstract Alterations in intrahepatic carbohydrate fluxes in ob/ob mice and the effects of acute leptin administration were studied in vivo by use of a dual-isotope tracer infusion. Metabolic sources of plasma glucose (gluconeogenesis (GNG) and glycogenolysis) and hepatic glycogen (GNG, direct synthesis and pre-existing) were determined in 20-h-fasted mice infused with [2-13C1]glycerol and [U13C6]glucose for 3 h. Total glucose output (TGO) and the rate of appearance (Ra) of plasma glycerol were measured by isotope dilution. GNG, the direct pathway of hepatic glycogen synthesis and hepatic triose-phosphate flux were determined by mass isotopomer distribution analysis (MIDA). Serum glucose, insulin, leptin and liver glycogen concentrations were also measured. After a 24-h fast, ob/ob mice had 2-fold higher TGO, 2.5-fold elevated liver glycogen content and markedly higher glycogenolytic flux to glucose, absolute GNG and direct glycogen synthesis rates (10-fold increased) compared to the control group. Ob/ob mice also had elevated triose-phosphate flux compared to controls (40 vs. 22 mg/kg lean body mass/min). A model of intrahepatic flux distributions in control and ob/ob mice is presented. In summary, elevated fasting plasma glucose concentrations are due to increased TGO in ob/ob mice, which is maintained by both increased GNG and increased glycogenolysis. Furthermore, the ob/ob mice have major alterations in fasting hepatic carbohydrate fluxes into triose-phosphate pools and glycogen. We support the model that actions of leptin on hepatic glucose metabolism require insulin or other factors.     

3,4-Methylenedioxymethamphetamine (ecstasy)-induced hepatotoxicity: effect on cytosolic calcium signals in isolated hepatocytes

Abstract: Aims/Background: Hepatocellular damage has been reported as a consequence of 3,4-methylenedioxymethamphetamine (MDMA) intake. However, little is known about the cellular mechanisms involved. The present study was undertaken to evaluate the effects of MDMA on cell viability as well as free calcium levels ([Ca²⁺]_i) in short-term cultured hepatocytes. Reduced glutathione (GSH), adenosine-5′-triphosphate (ATP) and lipid peroxidation were investigated to evaluate the toxic effect of MDMA, in vitro, using freshly isolated rat hepatocytes. Methods: In order to measure cytosolic free Ca²⁺ concentrations ([Ca²⁺]_i), rat hepatocytes were loaded with the Ca²⁺ indicator fura-2-acetoxymethylester (fura-2-AM). Results: A sustained rise of ([Ca²⁺]_i) after incubation with MDMA was the most noteworthy finding. In Ca²⁺-free medium, MDMA caused a reduced increase of ([Ca²⁺]_i). On the other hand, MDMA (0.1–5 mM) induced a concentration-dependent and time exposure-dependent GSH and ATP depletion. Although it did not reach statistical significance, GSH deficits were accompanied by a tendency to increase lipid peroxidation 3 h after MDMA incubation. Conclusions: The above data suggest that the marked rise of ([Ca²⁺]_i) and subsequent ATP and GSH depletion can lead to a rapid decrease in cell viability.     

Silymarin protects against acute ethanol-induced hepatotoxicity in mice

BACKGROUND: Accumulated evidence has demonstrated that both oxidative stress and abnormal cytokine production, especially tumor necrosis factor-alpha (TNF), play important etiological roles in the pathogenesis of alcoholic liver disease (ALD). Agents that have both antioxidant and anti-inflammation properties, particularly anti-TNF production, represent promising therapeutic interventions for ALD. We investigated the effects and the possible mechanism(s) of silymarin on liver injury induced by acute ethanol (EtOH) administration. METHODS: Nine-week-old mice were divided into 4 groups, control, silymarin treatment, EtOH treatment, and silymarin/EtOH treatment, with 6 mice in each group. Because control and silymarin values were virtually identical, only control treatment is shown for ease of viewing. Ethanol-treated mice received EtOH [5 g/kg body weight (BW)] by gavage every 12 hours for a total of 3 doses. Control mice received an isocalorical maltose solution. In the silymarin/EtOH group, silymarin was dissolved in the EtOH and gavaged simultaneously with EtOH at a dose of 200 mg/kg BW. At 4 hours after the last dosing, the mice were anesthetized and subsequent serum alanine aminotransferase (ALT) level, hepatic lipid peroxidation, enzymatic activity of hepatic cytochrome P450 2E1, hepatic TNF-alpha, and glutathione (GSH) levels were measured. Histopathological change was assessed by hematoxylin and eosin staining. RESULTS: Acute EtOH administration caused prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. Supplementation with a standardized silymarin attenuated these adverse changes induced by acute EtOH administration. CONCLUSIONS: Silymarin protects against the liver injury caused by acute EtOH administration. In view of its nontoxic nature, it may be developed as an effective therapeutic agent for alcohol-induced liver disease by its antioxidative stress and anti-inflammatory features.     

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

Summary The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (1.5mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-³H-glucose turnover were 20–25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41±4 vs 8±6 mol·min^–1·kg^–1. p < 0.001) but did not further decrease 3-³H-glucose turnover. Elevated nonesterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability. Increased glycogen synthesis, however, compensates for decreased glycolytic flux so that glucose turnover is not decreased. When liver glycogen stores are high, an acute increase in non-esterified fatty acid availability impairs suppression of hepatic glucose output. A chronic increase in non-esteriefid fatty acid availability may lead to insulin resistance by increasing glycogen stores.     

Amelioration of alloxan induced diabetes mellitus and oxidative stress in rats by oil of Eruca sativa seeds

Clinical research has confirmed the efficacy of several plant extracts in the modulation of oxidative stress associated with diabetes mellitus (DM). Oil of Eruca sativa seeds (ESS) is tried for prevention and treatment of DM induced experimentally by alloxan injection. A single dose of alloxan (100 mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides and cholesterol, decreased high-density lipoprotein and hepatic glycogen contents and elevated hepatic glucose-6-phosphatase activity. Concurrent with these changes, there was an increase in the concentration of malondialdehyde and 4-hydroxynonenal in the liver. This oxidative stress was related to a decreased glutathione (GSH) content and superoxide dismutase activity in the liver of alloxan-diabetic rats. ESS oil (0.06 ml/kg) on its own increased significantly hepatic GSH. Daily oral administration of ESS oil 2 weeks before or after diabetes induction ameliorated hyperglycemia, improved lipid profile, blunted the increase in malondialdehyde and 4-hydroxynonenal and stimulated the GSH production in the liver of alloxan-treated rats. We suggested that ESS oil could be used as antidiabetic complement in case of DM. This may be related to its antioxidative properties and to the increase in hepatic GSH.     

Hepatic stimulator substance administration ameliorates liver regeneration in an animal model of fulminant hepatic failure and encephalopathy

Abstract: Aims/Background: Hepatic stimulator substance (HSS) is a liver‐specific growth factor implicated in hepatocellular proliferation and hepatoprotection in models of acute liver injury. In the present study, we examined the effect of exogenous HSS administration on liver proliferating capacity and survival outcome in an experimental animal model of fulminant hepatic failure (FHF) and encephalopathy, induced by repeated injections of thioacetamide (TAA) in rats. Methods: Fulminant hepatic failure was induced in adult male Wistar rats by three consecutive intraperitoneal injections of TAA (400 mg/kg of body weight), at 24 h time intervals. The animals received intraperitoneally either a saline solution or HSS (50 mg protein/kg of body weight), 2 h after the second and third TAA injections. The animals were killed at 6, 12 and 18 h post the last injection of TAA. Results: Levels of liver enzymes and urea in serum, blood ammonia values, liver histology, stage of hepatic encephalopathy and survival were statistically significantly improved in TAA‐intoxicated and HSS‐treated rats compared to TAA‐intoxicated and saline‐treated ones. Furthermore, HSS ameliorated liver regenerative indices – DNA biosynthesis, thymidine kinase activity and hepatocyte mitotic activity – in a statistically significant manner. Conclusions: Our data suggest the beneficial effect of HSS administration in this animal model of FHF and encephalopathy, supporting evidence for a possible use of HSS as supportive therapy, by increasing hepatocellular proliferation, in management of FHF.     

Effect of in situ hypothermic perfusion on intrahepatic pO2 and reactive oxygen species formation after partial hepatectomy under total hepatic vascular exclusion in pigs

Abstract: Aim: This study examined attenuation of ischemia and reperfusion (I/R) induced liver injury during liver resections by hypothermic perfusion of the liver under total hepatic vascular exclusion (THVE). Method: Reactive oxygen species (ROS) formation, microcirculatory integrity and endothelial cell damage were investigated. Left hemihepatectomy (LHX) was performed without in situ perfusion (control‐LHX, n = 5) or with concomitant in situ perfusion with hypothermic (4 °C) Ringer‐glucose (cold‐LHX, n = 5) or normothermic (38 °C) Ringer‐glucose (warm‐LHX, n = 5). Glutathione (GSH) and malondialdehyde (MDA) concentrations, tissue pO₂ levels and hyaluronic acid (HA) uptake capacity were determined. Results: After cold, warm and control‐LHX, 24 h survival was 5/5, 0/5 and 3/5, respectively. GSH levels were best preserved after cold‐LHX during reperfusion. MDA levels increased in all groups without significant differences between the groups during reperfusion. Tissue pO₂ levels increased after cold‐LHX whereas after warm‐LHX and control‐LHX, pO₂ levels decreased during reperfusion. HA uptake capacity remained normal after cold‐LHX. After warm‐LHX and control‐LHX, HA uptake capacity decreased after 6 h of reperfusion but recovered after 24 h of reperfusion in the control‐LHX group. Conclusion: Moderate hypothermic perfusion protects the liver from I/R injury during LHX under THVE. This protective effect depended on maintenance of liver microcirculation rather than a reduction in ROS formation.     

小鼠急性酒精性肝损伤模型的建立

目的:建立一次性暴饮小鼠急性酒精性肝损伤模型,并动态研究肝脏病理形态学、氧化应激因子、炎症因子的变化.方法:将48只ICR小鼠随机分成2组,空白对照组一次性给予等热量、等体积的糖水6 g/kg灌胃,模型组一次性给予50%乙醇(6 g/kg)体质量灌胃,分别于灌胃后1.5、3、6、12 h动态监测小鼠血清谷丙转氨酶(alanine aminotransferase,ALT)、甘油三酯(triglyceride,TG),肝组织匀浆丙二醛(malondialdehyde,MDA)、还原型谷胱甘肽(reduced glulathione hormone(GSH)、超氧化物歧化酶(superoxide dismutase,SOD),及肝组织白介素-1β(interleukin 1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)表达;肝组织HE染色、苏丹Ⅲ染色观察肝组织形态学、脂肪变性程度.结果:成功复制了一次性暴饮50%乙醇(6 g/kg)的小鼠急性肝损伤模型,小鼠无死亡,出现翻正反射消失、嗜睡等醉酒状态.模型组小鼠血清ALT、TG水平随时间逐渐升高,6 h达峰值,12 h略下降;肝匀浆GSH含量6 h降至最低;造模后1.5 h肝脏SOD含量下降最为显著,下降约24%;1.5 h肝脏MDA含量上升最为显著,上升至正常组的2.2倍;肝脏IL-1β、TNF-α水平升高,12 h达峰值;HE染色结果示,造模后12 h可见中央静脉及小叶间经脉周围出现肝细胞肿胀、水样变性等病理改变;苏丹Ⅲ染色结果显示随着造模时间延长肝脂肪变性程度加重.结论:此模型造模周期短、易复制、稳定性好,是研究急性酒精性肝损伤发病机制和筛选药物的理想模型.     

Antihyperglycemic action of angiotensin II receptor antagonist,valsartan, in streptozotocin-induced diabetic rats

OBJECTIVES: In the present study, we use valsartan, a highly selective antagonist for angiotensin(1) (AT(1)) receptor subtype, to investigate the effect of AT(1) receptor on the plasma glucose metabolism in streptozotocin-induced diabetic rats (STZ-diabetic rats). METHODS: The plasma glucose concentration was assessed by glucose oxidase method and plasma insulin was measured using enzyme-linked immunosorbent assay. Systolic blood pressure (SBP) was determined by the tail-cuff method. The intravenous glucose challenge test (IVGCT) was carried out to evaluate the effect of valsartan on the glucose utilization in vivo. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis. Moreover, the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis. RESULTS: A single intravenous injection of valsartan decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Plasma glucose-lowering action of valsartan also observed in normal rats although in a way not so effective as that in STZ-diabetic rats. Valsartan at the dose of 0.2 mg/kg that produced the maximal plasma glucose-lowering activity in STZ-diabetic rats is also effective to lower the SBP. However, oral treatment with nifedipine or nicorandil in STZ-diabetic rats at the dose sufficient to decrease SBP showed no change of plasma glucose. Otherwise, infusion of saralasin (10 microg/kg per min) into STZ-diabetic rats produced a plasma glucose-lowering activity similar to that by valsartan at 0.2 mg/kg. Moreover, valsartan (0.2 mg/kg) significantly attenuated the raise of plasma glucose induced by IVGCT in normal rats. Repeated intravenous administration of valsartan (0.2 mg/kg) in STZ-diabetic rats resulted in the lowering of plasma glucose after 3 days. The mRNA and protein levels of GLUT4 in the soleus muscle were increased after repeated intravenous administration of valsartan in STZ-diabetic rats for 3 days. Moreover, similar repeated treatment with valsartan reversed the elevated mRNA and protein levels of PEPCK in the liver of STZ-diabetic rats. CONCLUSIONS: These results suggest that the plasma glucose-lowering activity of AT(1) receptor antagonism was associated with an increase in the glucose utilization in peripheral tissue and/or a reduction in hepatic gluconeogenesis in the absence of insulin.     

己酮可可碱对日本血吸虫病肝纤维化小鼠肝脏TGF- β1和Ⅰ、Ⅱ型胶原表达的影响

目的　研究己酮可可碱 (pentoxifylline,PTX)对日本血吸虫病肝纤维化小鼠肝脏转化生长因子β1(TGF-β1)和 、 型胶原含量的影响。　方法　 4 0只血吸虫病肝纤维化小鼠均分 4组 ,对照组不作任何治疗。吡喹酮组 5 0 0mg/ (kg· d)治疗 2 d,高剂量 PTX组 36 0 mg/ (kg· d)治疗 8wk,低剂量 PTX组 180 mg/ (kg· d)治疗 8wk。应用免疫组化染色方法和多媒体彩色病理图文分析系统 ,观察不同剂量 PTX治疗前后肝脏 TGF-β1和 、 型胶原含量的变化。　结果　 PTX对 TGF- β1和 、 型胶原含量的影响与治疗剂量有关 ,高剂量 PTX组 TGF- β1和 、 型胶原含量明显低于对照组 (P<0 .0 1) ,而低剂量 PTX组与对照组之间差异无统计学意义 (P>0 .0 5 )。　结论　高剂量 PTX治疗血吸虫病肝纤维化小鼠可显著降低其肝脏 TGF-β1和 、 型胶原的含量。     

Phospholipids Prevent Enteric Bacterial Translocation in the Early Stage of Experimental Acute Liver Failure in the Rat

Wang XD, Andersson R, Soltesz V, Wang WQ, Ar'Rajab A, Bengmark S. Phospholipids prevent enteric bacterial translocation in the early stage of experimental acute liver failure in the rat. Scand J Gastroenterol 1994;29:1117-1121.

Background: Bacterial infections and bacteremia in acute liver failure may at least partly be attributed to translocation of enteric bacteria. Attempts to prevent or treat such infections by the use of antibiotics may instead result in overgrowth of surviving microbes.

Methods: In the present study, normal saline (1.5 ml/100 g body weight), phosphatidylcholine (1.5 ml/100 g body weight), and phosphatidylinositol (1.5 ml/100 g body weight) were orally administered by means of a gastric tube both 12 h and 30min before operation. Effects of enteric administration of phospholipids on the prevention of enteric bacterial translocation, intestinal and mucosal mass, and enterocyte protein contents in acute liver failure induced by subtotal liver resection in the rat were evaluated.

Results: The incidence of bacterial translocation increased significantly 2 and 4h after 90% hepatectomy as compared with sham-operated animals. Enteric administration of phospholipids, however, significantly reduced the incidence of bacterial translocation after 90% hepatectomy. Phospholipid treatment prevented the postoperative decrease in intestinal mucosal mass and enterocyte protein content.

Conclusions: Enteral administration of phospholipids thus seems to protect against translocation of enteric bacteria and prevent against a decrease in intestinal mucosal mass and enterocyte protein content after subtotal hepatectomy in the rat.     

不同剂量还原型谷胱甘肽对大鼠急性肝损伤的修复作用

目的探讨不同剂量的还原型谷胱甘肽对大鼠急性肝损伤的修复作用。方法用四氯化碳诱导大鼠急性肝损伤,给予不同剂量还原型谷胱甘肽腹腔注射,7天后处死大鼠,观察血清转氨酶AST、ALT及HE染色观察肝脏病理形态。结果肝损伤模型组与对照组相比血清转氨酶明显升高,肝细胞广泛脂肪变性。还原型谷胱甘肽组的转氨酶高于模型组,肝脏细胞肿胀、脂肪变性程度均明显低于模型组,但还原型谷胱甘肽小剂量组与加倍剂量组之间无显著差异。结论还原型谷胱甘肽对大鼠急性肝损伤有修复作用,但增加药物剂量并不能增强其对肝损伤的修复作用。     

Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, protects liver against carbon tetrachloride-induced oxidative stress in transgenic mice expressing the hepatitis C virus polyprotein.

BACKGROUND/AIM: Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, has been used as a treatment for chronic hepatitis for more than 30 years in Japan, and shown to be effective in preventing the development of hepatocellular carcinoma in chronic hepatitis C patients, but its underlying mechanisms remain elusive. The aim of this study was to investigate if SNMC had an anti-oxidative effect, as oxidative stress has been proposed to be one of the mechanisms of liver injury in hepatitis C virus (HCV)-associated chronic liver diseases. METHODS: The protective effect of SNMC against carbon tetrachloride (CCl4)-induced liver injury was examined using transgenic mice expressing the HCV polyprotein. RESULTS: A small dose of CCl4 (10 microl/kg of body weight) significantly increased the serum alanine aminotransferase (ALT) level and hepatic malondialdehyde content, decreased hepatic reduced glutathione (GSH) content and induced ultrastructural alterations of hepatic mitochondria in transgenic mice, but not in nontransgenic mice. A single SNMC treatment equivalent to a clinical dose significantly restored the serum ALT level and hepatic malondialdehyde and GSH contents, attenuated the ultrastructural alterations of hepatic mitochondria, and increased mRNA expression of gamma-glutamylcysteine synthetase (gamma-GCS). CONCLUSIONS: Transgenic mice expressing the HCV polyprotein are abnormally vulnerable to oxidative stress. SNMC protects hepatocytes against CCl4-induced oxidative stress and mitochondrial injury in the presence of HCV proteins by restoring depleted cellular GSH.     

Platelet-Activating Factor Inactivator (rPAF-AH) Enhances Liver’s Recovery After Paracetamol Intoxication

Platelet-activating factor (PAF) is a potent endogenous phospholipid modulator of diverse biological activities, including inflammation. The aim of this study was to investigate the effects of PAF inactivator, recombinant PAF acetylhydrolase (rPAF-AH) on post–paracetamol treatment functional outcome of the liver in the rat. Fifty male Wistar rats were divided into two groups: the control group received by gastric tube a toxic dose of paracetamol (3.5 g/kg body weight) and the rPAF-AH-treated group received the same dose of paracetamol followed by a dose of rPAF-AH (10 mg/kg body weight) intraperitoneally. The animals were sacrificed at 8, 16, 24, 32, and 40 hr after paracetamol treatment. APAP was found to cause acute hepatic injury, evident by alterations of biochemical (serum enzymes: ALT, AST, and ALP) and liver histopathological (degree of inflammation and apoptosis) indexes, which was followed by liver regeneration evident by three independent indexes ([³H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, and hepatocyte mitotic index). Hepatic levels of malondialdehyde (MDA) and serum cholesterol/HDL cholesterol fraction were also measured as parameters of oxidant-antioxidant balance. The positive effects of rPAF-AH were expressed by (1) a reduction of oxidative stress, (2) a large decrease in hepatic injury, and (3) a reduction of regenerating activity. These results suggest that PAF plays an important role in paracetamol-induced liver injury and regeneration. Furthermore, PAF inactivator enhances liver’s recovery and attenuates the severity of experimental liver injury, providing important means of improving liver function following paracetamol intoxication.     

Trajectories of glycaemic traits exhibit sex-specific associations with hepatic iron and fat content: Results from the KORA-MRI study

Background

Non-alcoholic fatty liver disease (NAFLD) represents a major disease burden in the population. While the bidirectional association between NAFLD and diabetes is established, little is known about the association of hepatic iron content and glycaemia. Moreover, analyses of sex-specific effects and of dynamic changes in glycaemia are scarce.

Methods

We investigated 7-year sex-specific trajectories of glycaemia and related traits (HbA1c, fasting glucose, fasting insulin, HOMA-IR, 2-h glucose and cross-sectional 2-h insulin) in a sample from a population-based cohort (N = 365; 41.1% female). Hepatic iron and fat content were assessed by 3T-Magnetic Resonance Imaging (MRI). Two-step multi-level models adjusted for glucose-lowering medication and confounders were applied.

Results

In women and men, markers of glucose metabolism correlated with hepatic iron and fat content. Deterioration of glycaemia was associated with increased hepatic iron content in men (normoglycaemia to prediabetes: beta = 2.21 s⁻¹, 95% CI [0.47, 3.95]). Additionally, deterioration of glycaemia (e.g. prediabetes to diabetes: 1.27 log(%), [0.84, 1.70]) and trajectories of glucose, insulin and HOMA-IR were significantly associated with hepatic fat content in men. Similarly, deterioration of glycaemia as well as trajectories of glucose, insulin and HOMA-IR was significantly associated with increased hepatic fat content in women (e.g. trajectory of fasting insulin: 0.63 log(%), [0.36, 0.90]).

Conclusions

Unfavourable 7-year trajectories of markers of glucose metabolism are associated with increased hepatic fat content, particularly in women, whereas the association with hepatic iron content was less clear. Monitoring changes of glycaemia in the sub-diabetic range might enable early identification of hepatic iron overload and steatosis.