Total parenteral nutrition (TPN) is an artificial way to support daily nutritional requirements by bypassing the digestive system, but long-term TPN administration may cause severe liver dysfunction. Glycyrrhizin is an active component of licorice root that has been widely used to treat chronic hepatitis. The aim of this study is to investigate the hepatoprotective effect of glycyrrhizin on TPN-associated acute liver injury in vivo. Liver dysfunction was induced by intravenous infusion of TPN at a flow rate of 20 mL/kg/h for three h in Sprague Dawley rats. The rats were pretreated with Glycyrrhizin (1, 3 and 10 mg/kg intravenously). After receiving TPN or saline (control group) for three h, the rats were sacrificed, blood samples were collected for biochemical analyses and liver tissue was removed for histopathological and immunohistochemical examination. We found that aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and triglyceride (TG) levels were significantly increased in the TPN group without glycyrrhizin pretreatment and decreased in the glycyrrhizin-pretreated TPN group in a dose-dependent manner. The stained liver sections showed that glycyrrhizin relieved acute liver injury. The upregulation of serum protein biomarkers of reactive nitrogen species, including nitrotyrosine and inducible NO synthase (iNOS), were attenuated by glycyrrhizin pretreatment. Levels of endoplasmic reticulum (ER) stress factors, such as phosphorylation of JNK1/2, p38 MAPK and CHOP, were decreased by glycyrrhizin pretreatment. In summary, our results suggest that glycyrrhizin decreases TPN-associated acute liver injury factors by suppressing endoplasmic reticulum stress and reactive nitrogen stress.

Previously, we found that Korean red ginseng suppressed acetaminophen (APAP)-induced hepatotoxicity via alteration of its metabolic profile involving GSTA2 induction and that ginsenoside Rg3 was a major component of this gene induction. In the present study, therefore, we assessed the protective effect of Rg3 against N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolic intermediate of APAP. Excess NAPQI resulted in GSH depletion with increases in the ALT and AST activities in H4IIE cells. Rg3 pretreatment reversed GSH depletion by NAPQI. Rg3 resulted in increased mRNA levels of the catalytic and modulatory subunit of glutamate cysteine ligase (GCL), the rate-limiting steps in GSH synthesis and subsequently increased GSH content. Rg3 increased levels of nuclear Nrf2, an essential transcriptional factor of these genes. The knockdown or knockout of the Nrf2 gene abrogated the inductions of mRNA and protein by Rg3. Abolishment of the reversal of GSH depletion by Rg3 against NAPQI was observed in Nrf2-deficient cells. Rg3 induced multidrug resistance-associated protein (Mrp) 1 and Mrp3 mRNA levels, but not in Nrf2-deficient cells. Taken together, these results demonstrate that Rg3 is efficacious in protecting hepatocytes against NAPQI insult, due to GSH repletion and coordinated gene regulations of GSH synthesis and Mrp family genes by Nrf2.

Dehydration can be extremely damaging to the performance and welfare of indigenous chickens. The effect of water restriction on haematological and biochemical parameters was compared in Naked Neck (NNK) and Ovambo (OVB) chickens. A total of 54 8-week-old pullets each of NNK and OVB chickens with an initial average weight of 641 ± 10 g/bird were randomly assigned to three water intake treatments with three replications, each having six birds. The water restriction treatments were ad libitum, 70% and 40% of ad libitum intake. Nine experimental pens with a floor space of 3.3 m2 per strain were used. Feed was provided ad libitum. Packed cell volume (PCV), erythrocyte count (RBC), mean corpuscular volume (MCV) and total leucocyte count (WBC), and biochemical parameters (uric acid (UA)), creatinine (CREAT), total protein (TP), albumin (ALB), globulin (GLOB), triglyceride (TGA), total cholesterol (TC), high- (HDLC) and low- (LDLC) density lipoprotein cholesterol and activity of alanine transaminase (ALT), alkaline phosphatase (ALP) and aspartate transaminase (AST) were determined from blood collected after 60 days of water restriction. PCV was higher (P < 0.05) in NNK than OVB chickens offered water ad libitum, but similar in birds offered 70% and 40% of ad libitum. There were no differences in RBC and MCV values between strains, but MCV was higher in birds on 40% than 70% of ad libitum water intake, irrespective of strain. Naked neck chickens had higher (P < 0.05) WBC values than OVB at 40% restriction level, but lower WBC than OVB at 70% water restriction level. UA, CREAT, TGA, TC, LDLC, TP and GLOB increased (P < 0.05) with each increment in water restriction, but the increase in CREAT and TC was more pronounced in OVB than NNK chickens. The opposite was observed for UA. ALT activity indicated that liver function was not affected by water restriction. It was concluded that the two strains can withstand up to 40% of ad libitum water restriction, but NNK tolerated water stress better than OVB chickens.

Fluoride is ubiquitously distributed in natural waters. Elevated fluoride may cause histopathological changes and induce oxidative stress in the gills of the common carp (Cyprinus carpio). The present study further evaluates the effects of fluoride on growth performance, body composition and biochemical measurements of C. carpio. Our results showed that food intake, growth, serum osmolality, body composition, and biochemical measures in the blood were affected by fluoride. Weight gain rate and specific growth rate in the exposed fish decreased compared with those of the control fish. Levels of crude protein and crude lipids were reduced the fluoride exposed fish. The major ion levels in the serums of fluoride-exposed fish were severely disturbed, resulting in a lower osmolality. All the biochemical parameters measured in the blood were affected by the exposure to fluoride. Total protein, albumin, globulin and glucose in fish exposed to 63.6, 77.7 and 124.4 mg/L were lower than those in the control fish. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly increased in exposed fish compared to the control ones. Taken together, exposure to fluoride caused a suite of detrimental effects in C. carpio, which might lead to a decrease in growth and food utilization efficiency. Our results implied that high levels of fluoride could pose a threat to carp in the field. Environ Toxicol Chem © 2013 SETAC.

Acrylamide (AA) forms during the heating of starchy foods at high temperature, and is regarded as a potential genotoxic carcinogen. However, with the worldwide concern about the carcinogenicity of AA, how to reduce the toxicity of AA has become a hot research topic. In this study, we further discussed the effects of oral administration of allicin on AA-induced toxicity by determining the hematological, biochemical and immunological parameters in the serum, kidney, liver, and brain of male mice. Our data showed that the orally administered allicin of 5, 10, and 20 mg kg(-1) bw d(-1) could significantly decrease thiobarbituric reactive substances (TBARS) and myeloperoxidase (MPO) levels, and simultaneously remarkably increased the superoxide dismutase (SOD) activity, glutathione S-transferase (GST) and glutathione (GSH) levels in the kidney, liver, and brain of the AA-treated mice. Furthermore, oral administration of allicin not only significantly decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), tumor necrosis factor α (TNF-α), interleukin (IL)-1β, interleukin (IL)-6, reactive oxygen species (ROS), and 8-hydroxy-desoxyguanosine (8-OHdG), but also increased interleukin (IL)-10 in the serum of AA-treated mice. Therefore, it was concluded that oral administration of allicin had a significant in vivo protective effect against the AA induced toxicity.

Total body irradiation (TBI) is a choice therapy for the management of some malignancies; it is also a major cause of oxidative stress. The aim of this research is to sequentially document the effect of total body radiation on body function utilizing the sequential changes in liver function enzymes and proteins in rats.Serum protein and liver enzymes were assessed using kits in rats exposed to total body radiations of 1.27 Gy/minute in cumulative doses to the fourth radiation at five-day intervals.Aspartate aminotransferase (AST), alanine transaminase (ALT) and serum protein were significantly (p < 0.05) elevated with increasing radiation. No significant differences between experimental and control groups for bilirubin concentrations were noted at any time. Serum levels of albumin were significantly (p < 0.05) increased with the first to third radiation exposures but reduced at the fourth cumulative dose exposure.Variations are associated with acute stress, inflammation which could be due to nonspecific stress reaction, while fluctuations could arise as a result of tolerance and repair within the liver These tests are significant for diagnosis of radiation-induced injury and can be important for evaluation of its severity and correct management.

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.

Puerarin (PR) has been utilized as a phytomedicine to managing liver disease in China. Thus, this study aimed to evaluate the potential PR-mediated hepatoprotective role against chronic alcohol-induced liver injury in rats. The results indicated that serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and pro-inflammatory cytokines were significantly reduced following PR treatment, while the albumin (ALB) level was increased. Meanwhile, intrahepatic contents of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) were elevated. Pathological examination showed that alcohol-lesioned hepatocytes were mitigated through the PR treatment. In addition, the endogenous levels of glycogen synthase kinase-3β (GSK-3β) at the protein level and β-catenin expression at the mRNA level were notably down-regulated, whereas the tumor necrosis factor alpha (TNF-α) and nuclear factor-kappa B (NF-κB) proteins in the liver tissue were effectively decreased following the PR treatment. Together, these findings demonstrate that PR mediates hepatoprotection against alcohol-induced liver injury. The mechanisms underlying the cytoprotective effects of PR are associated with inhibiting immunotoxicity in hepatocytes and regulating the GSK-3β/NF-κB pathway, thereby maintaining metabolic homeostasis in the liver tissue.

BACKGROUND:

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis.

AIMS:

We evaluated the beneficial effect and molecular mechanism of Korean red ginseng (KRG) on the APAP-mediated hepatotoxicity and identified a major component of KRG for hepatoprotection.

METHODS:

Survival test, liver function test, histopathological study, APAP-metabolic profiling and gene expression were examined in mice. We determined the enzyme expression and upstream signalling in H4IIE cells analysed by RT-PCR, immunoblotting, siRNA gene knockdown and promoter-luciferase assay.

RESULTS:

High doses of KRG reduced mortality at the LD50 of APAP. APAP increased AST and ALT activities, which were abrogated by low doses of KRG. These protective effects were consistent with the results from histopathological examinations. KRG altered APAP metabolic profiles through inhibition of cytochrome P450 2E1 and induction of glutathione S-transferase A2 (GSTA2). Knockdown of GSTA2 catalyses the conjugation of glutathione reversed KRG-mediated protection against N-acetyl-p-benzoquinone imine in H4IIE cells. The nuclear Nrf2 and C/EBPβ, which are essential transcriptional factors for GSTA2 were increased by KRG. These effects were downstream of multiple signalling, including PI3K, JNK or PKA. Ginsenoside Rg3 but not Rb1, Rc and Rg1 significantly increased GSTA2 protein expression. Rg3 resulted in the transcriptional activation of GSTA2 downstream of the multiple cellular signalling.

CONCLUSIONS:

These results demonstrate that KRG is efficacious in protection against APAP-induced hepatotoxicity and mortality through metabolic regulation and that Rg3 is a major component of KRG for the GST induction, implying that Rg3 should be considered to be a potential hepatoprotective agent.

AIM:

d-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB; Vaccinium corymbosum L.) treatment on oxidative stress in age-related liver injury model.

METHODS:

Rats received GAL (300 mg/kg, s.c.; 5 days per week) alone or together with 5% (BB1) and 10% (BB2) BB-containing chow for 2 months. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and hepatic malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels, and CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and glutathione transferase (GST) activities together with mRNA expressions of SOD1, GPx1, MnSOD (SOD2) and phospholipid hydroperoxide glutathione peroxidase (GPx4) were determined in GAL-treated rats.

RESULTS:

MDA and PC levels increased, but GSH levels, SOD1 and GPx1 activities decreased together with histopathological structural damage in the liver in GAL-treated rats. There was no change in hepatic mRNA expressions of SOD2 and GPx1, but SOD1 and GPx4 expressions decreased. BB1 and BB2 caused significant decreases in serum ALT and AST activities together with the amelioration in histopathological findings in GAL-treated rats. Both BB1 and BB2 reduced MDA and PC levels, and elevated GSH levels, and SOD1 and GPx1 activities. However, hepatic mRNA expressions of SOD1, SOD2, GPx1 and GPx4 remained unchanged in GAL-treated rats.

CONCLUSIONS:

These results show that BB restored liver pro-oxidant status together with histopathological amelioration by acting as an anti-oxidant (radical scavenger) itself without affecting mRNA expressions of anti-oxidant enzymes in GAL-treated rats. Geriatr Gerontol Int 2013; ●●: ●●-●●.