• BMB Reports
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• v.52 no.3
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• pp.190-195
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• 2019

Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an $NAD^+$-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirt2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP-mediated endoplasmic reticulum (ER) stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries.

• Nutrition Research and Practice
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• v.15 no.2
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• pp.187-202
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• 2021

BACKGROUND/OBJECTIVES: The exposure to sucrose in rats has mimic abnormalities attributed to metabolic syndrome (MetS). The effects of honey bee and "free" glucose and fructose, have not been explored in this context. The aim was to expose Wistar rodents to sucrose solution (SS), honey solution (HS) and fructose/glucose solution (GFS) at 30% to assess their effects. SUBJECTS/METHODS: HS (n = 10), SS (n = 10) and GFS (n = 10) groups were formed. Solutions were ad libitum along 14-weeks. RESULTS: Between solutions consumptions, honey was significantly 42% higher (P = 0.000), while similar consumption was observed among GFS and SS. The feeding pattern of HS consumption was irregular along experiment; while the food intake pattern showed the similar trend among groups along time. Non statistical differences were obtained in any biochemical and anthropometric measure, however, a higher concentration of leptin (721 ± 507 pg/mL), lower concentration of total cholesterol (TC; 48.87 ± 2.41 mg/100 mL), very low density lipoprotein (VLDL; 16.47 ± 6.55 mg/100 mL) and triglycerides (82.37 ± 32.77 mg/100 mL) was obtained in SS group. For anthropometric values, HS showed less total adipose tissue (AT; average 26 vs. 31-33 g) and adiposity index (average 6.11 vs. 7.6). Due to sugar-sweetened beverages consumption increases the risk for the development of chronic diseases; correlations between fluid intake and anthropometric and biochemical parameters were assessed. A moderate correlation was obtained in groups with the weight of total AT and solution intake; for the weight gain in GFS group and for triglycerides in HS and GFS. The highest hepatic tissue damage was observed in SS group with multiple intracytoplasmic vacuoles, atypia changes, moderate pleomorphism and hepatocellular necrosis. CONCLUSIONS: In spite of the significantly higher consumption of HS, biochemical, anthropometrical and histological effects were not remarkably different in comparision to other sweeteners.

• Journal of the Korean Society of Food Science and Nutrition
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• v.34 no.9
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• pp.1344-1349
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• 2005

The aim of this study was to evaluate the effects of Welsh onion administration on $CCl_4$-induced hepatic injury in rats. The increasing rate of the body and organ weight was not significantly different by the ad-ministration of the Welsh onion. Welsh onion (2, 4, $10\%$ w/w) was given for 4 weeks with the injections of $CCl_4$. Total serum lipid was significantly decreased in all treatment groups compared to $CCl_4$ only treatment group (p<0.05). The Welsh onion from winter season was more protective effect by lowering the serum levels of transminase (SGOT and SGPT) compared with others, the levels of transminase - phosphatase (ALP) in serum. The Welsh onion from winter at a dose of $4\%,\;10\%$ (w/w) showed significantly hepatoprotective activity which was comparable to that $CCl_4$-induced hepatic damage. Histological evaluation showed that Welsh onion partially prevented $CCl_4$-induced inflammation, necrosis and vacuolation. Pretreatment of Welsh onion reduced extent of the necrosis found 24 hr after the intraperitoneal administration of $CCl_4$. The present study shows the liver protective action of the Welsh onion against experimentally induced liver damage in rats. This suggests that the Welsh onion may be used as an effective hepatoprotective agent.

• Journal of Veterinary Clinics
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• v.14 no.2
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• pp.308-318
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• 1997

The present experiment was performed in order to know the treatment effect of aquapuncture with hepatonics on recovery in artificially induced hepatic damaged dogs by carbon tetrachloride. The animals were divided into a control and two experimental groups (aquapuncture with taurine into Gan-su acupoint: Aa-I group and aquapuncture with taurine into blank acupoint in the thigh: Aa-II group). The changes of serum enzyme activities (ALT, AST and ALP), serum total protein contents, protein fractions and pathohistological findings of the liver were examined after application of aquapunctiuf treauent The results obtained through this experiment were summarized as follows : The serum ALT activities tendeded to decrease in experimental group compared with those of control group. Significances were detected at 5th (p<0.05) and 7th (p<0.05) day in Aa-I group and 7th day (p<0.05) in Aa-II group, respectively. Low value was fecund in Aa-I group compared with Aa-II groups but significance was not observed between two experimental groups. The serum AST activities in experimental group showed decreasing tendency compared with those of control group. Significances were observed at 2nd (p<0.05) and 5th (p<0.05) day in Aa-I group and 2nd (p<0.05) day in Aa-II groups respectively. Aa-I group showed lower values than those of Aa-II groups however, no significance was detected between experimental groups. The serum ALP activities of experimental group showed a slight decrease compared with those of control group, however, significance was not detected among all groups. The serum total protein content in experimental group showed tendency of increase compared with control group. Significance was found at 2nd day (p<0.05) in Aa-I group, but there was no significance in Aa-II group. Further significant increase of total protein content was seen at 1st day (p<0.05) in Aa-I group compared with Aa-II group. The change of serum albumin content in experimental group showed tendency of increase compared with control. Significant increases were detected at 1st (p<0.01) and 2nd (p<0.01) day in Aa-I group, respectively. Aa-II group showed increase compared with control groups but significance was not observed. Further significant increase was at 1st day (p <0.05) in Aa-I group compared with Aa-II group. The change of ${\beta} $-globulin in Aa-I group was slightly decreased compared with control group. Aa-II group was similar to controls but significance was not observed among all groups. The change of P-globulin content in Aa-I group showed tendency of increase compared with control and Aa-II group showed the tendency of decrease compared with control. The change of ${\gamma}$-globulin content experimental group showed tendency of increase compared with control, however, significance was not detected among groups. The change of A/G ratio in Aa-I group showed tendency of increase compared with control group and Aa-II group was similar to controls but no significance was found among groups. As for pathohistological observations the grade of hepatocellular vacuolized degeneration and necrosis in Aa-I group was milder than those of control and Aa-II groups and the change of Aa-II group was similar to that of control. Considering above finding collectively, it was thought that aquapuncture of Gan-su acupoint with hepatonics was more effective than aquapuncture of blank acupoint for the recovery of hepatic damage.

• Journal of Nutrition and Health
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• v.48 no.5
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• pp.390-397
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• 2015

Purpose: In this study, we investigated the effects of chronic alcohol and excessive iron intake on mitochondrial DNA (mtDNA) damage and the progression of alcoholic liver injury in rats. Methods: Twenty-four Sprague-Dawley male rats were divided into four groups (Control, EtOH, Fe, and EtOH + Fe), and fed either control or ethanol (36% of total calories) liquid diet with or without 0.6% carbonyl iron for eight weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, liver malondialdehyde concentrations were measured by colorimetric assays. Liver histopathology was examined by Hematoxylin-eosin staining of the fixed liver tissues. The integrity of the hepatic mtDNA and nuclear DNA was measured by long-range PCR. The gene expression levels of cytochrome c oxidase subunit 1 (Cox1) and NADH dehydrogenase subunit 4 (Nd4) were examined by real-time PCR. Results: Serum ALT and AST activities were significantly higher in the EtOH+Fe group, as compared to the Control group. Similarly, among four groups, liver histology showed the most severe lipid accumulation, inflammation, and necrosis in the EtOH + Fe group. PCR amplification of near-full-length (15.9 kb) mtDNA showed more than 50% loss of full-length product in the liver of the EtOH + Fe group, whereas amounts of PCR products of a nuclear DNA were unaffected. In addition, the changes in the mtDNA integrity showed correlation with reductions in the mRNA levels of mitochondrial gene Cox1 and Nd4. Conclusion: Our data suggested that the liver injury associated with excessive iron and alcohol intake involved mtDNA damage and corresponding mitochondrial dysfunction.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.17 no.6
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• pp.207-214
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• 2016

This study determined the effect of Lespedeza Caneata extract on the livers and kidneys of lead-administered mice. The experimental groups were divided into a normal group, Pb 4W group, Pb-LC 4W group, Pb 8W group, and Pb-LC 8W group. The normal group was supplied single distilled water, and the pb group was provided distilled water in which lead acetate was dissolved at 1,000 ppm. The Pb-LC group was provided with lead as drinking water, and the Lespedeza Caneata was orally medicated at a concentration of 500 mg/kg daily. AST, ALT, and BUN enzyme activities and histological experiments on the livers and kidneys resulted in the following conclusions. AST, ALT, and BUN activities increased in the experimental group compared to the normal group and decreased more in the Pb-LC group than the pb group during the same period. The histological results reveal that portions of the livers and kidneys were deformed in the Pb 4W group, and most of the Pb 8W group experienced necrosis and deformation. pb-LC4W and Pb-LC 8W groups experienced less deformation than the Pb 4W and Pb 8W groups. During the same period, the Pb-LC group experienced less histological changes than the Pb group. These results suggest that Lespedeza Caneata extract may have some protective effect on hepatic tissue and renal tissue damage with lead-administered in mice.

• Toxicological Research
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• v.34 no.1
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• pp.65-73
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• 2018

Pretreatment of low-dose lipopolysaccharide (LPS) induces a hyporesponsive state to subsequent secondary challenge with high-dose LPS in innate immune cells, whereas super-low-dose LPS results in augmented expression of pro-inflammatory cytokines. However, little is known about the difference between super-low-dose and low-dose LPS pretreatments on immune cell-mediated inflammatory and hepatic acute-phase responses to secondary LPS. In the present study, RAW 264.7 cells, EL4 cells, and Hepa-1c1c7 cells were pretreated with super-low-dose LPS (SL-LPS: 50 pg/mL) or low-dose LPS (L-LPS: 50 ng/mL) in fresh complete medium once a day for 2~3 days and then cultured in fresh complete medium for 24 hr or 48 hr in the presence or absence of LPS ($1{\sim}10{\mu}g/mL$) or concanavalin A (Con A). SL-LPS pretreatment strongly enhanced the LPS-induced production of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6, TNF-${\alpha}$/IL-10, prostaglandin E2 ($PGE_2$), and nitric oxide (NO) by RAW 264.7 cells compared to the control, whereas L-LPS increased IL-6 and NO production only. SL-LPS strongly augmented the Con A-induced ratios of interferon (IFN)-${\gamma}$/IL-10 in EL4 cells but decreased the LPS-induced ratios of IFN-${\gamma}$/IL-10 compared to the control, while L-LPS decreased the Con A- and LPS-induced ratios of IFN-${\gamma}$/IL-10. SL-LPS enhanced the LPS-induced production of IL-6 by Hepa1c1c-7 cells compared to the control, while L-LPS increased IL-6 but decreased IL-$1{\beta}$ and C reactive protein (CRP) levels. SL-LPS pretreatment strongly enhanced the LPS-induced production of TNF-${\alpha}$, IL-6, IL-10, $PGE_2$, and NO in RAW 264.7 cells, and the IL-6, IL-$1{\beta}$, and CRP levels in Hepa1c1c-7 cells, as well as the ratios of IFN-${\gamma}$/IL-10 in LPS- and Con A-stimulated EL4 cells compared to L-LPS. These findings suggest that pre-conditioning of SL-LPS may contribute to the mortality to secondary infection in sepsis rather than pre-conditioning of L-LPS.

• Journal of Veterinary Clinics
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• v.8 no.2
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• pp.127-142
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• 1991

This study was carried out to investigate fatty liver in Korean black goats. Adult female goats were divided into 3 test groups(A, B and C). Group A and B of goats each received 3 test consecutive daily doses of DL-ethionine at 75mg/kg and 150mg/kg body weight, respectively. Group C of goats was given 3 consecutive doses of the compound every 48 hours at 150mg/kg body weight. The clinical symptoms, hematological values, serum chemical values and histopathological study of the liver were investigated in the test animals. The results obtained are as follows ; 1. Fatty liver were observed in every test animal. 2. Some clinical symptoms( anorexia, depression) were appeared from 1st day to 7th day after administration of the compound in every test animal. In addition to these symptoms, diarrhea and salivation were generally observed in test animals which were given the compound at 150mg/kg body weight. The degree of these symptoms was dose dependent. 3. There was no significant variations in total WBC counts and fibrinogen values in the blood of test goats. The PCV values were significantly increased on 5th day of dosing in group A and B of goats. 4. The total lipid value was not changed but the concentration of NEFA was significantly increased on 3rd day of dosing with the compound and returned to normal value after 10 days hereafter. The value of triglycerides was significantly increased on 1st day and returned to normal value on 3rd day of dosing. The value of cholesterol was significantly decreased on 3rd day and returned to normal value on 10th day after treatment. 5. Total protein level was decreased on 10th day of dosing in the groups of B and C, and billirubin level was significantly increased on 7th day of dosing in every test group and returned to normal level after 13th day of administration. 6. The activity of GGT in serum was not changed while the activities of SDH and AST were significantly increased in every test goat and those values were returned to normal after 10~13th day of trestment. 7 The 35K-protein fraction in serum was not detected by SDS-polyacrylamide gel electrophoresis, but this protein fraction was detected by the same method after treating the 21st and 22nd fraction which were obtained by column chromatography with Sephadex G-100. 8. The affected liver was congested and swollen on 3rd day, and yellowish brown in color and mottled appearance on 7th day of treatment. Histopathologically, fat droplets were common in the hepatocytes, this change was intensive on 7th day after treatment in group B and C. Hepatic cell necrosis was observed in some livers but this pathological change was disappeared and returned to normal after 13 days of treatment.

• Toxicological Research
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• v.21 no.4
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• pp.339-345
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• 2005

Aflatoxins are produced by Aspergillus flavus, parasiticus that grows in improperly stored cereals. Aflatoxin $B_1\;(AFB_1)$ is a potent hepatocarcinogen in a variety of experimental animals including human beings. In spite of a high attention to the hepatocarcinogenecity of aflatoxins, the relative toxicity of other types $(AFB_2,\;AFG_1\;and\;AFG_2)$ of the toxins is not fully clarified. Sprague-Dawley male rats were orally administered with $AFB_1,\;AFB_2,\;AFG_1\;and\;AFG_2$ at the dose of 250, 1250, and $2500\;{\mu}g/kg$ body weight. Animals were then killed at 12, 24 or 48 hrs following aflatoxin adminstration. Subsequently the relative weight of liver was measured and histopathological examination on the liver was performed. Level of 8-OxodG and expression of ras gene in the liver was determined. The relative liver weights at high doses of $AFB_1\;and\;AFG_1$ was significantly low. The treatment of $AFB_1$ at the high dose of $2500\;{\mu}g/kg$ showed vacuolar degeneration and centrilobular hepatic necrosis with inflammatory cells. The pathological changes by $AFB_2\;AFG_1,\;and\;AFG_2$ were not clearly found. The formation of 8-OxodG by $AFB_1$ increased in a dose-dependent manner up to 24 hrs after a single treatment of $AFB_1$ thereafter decreased to the level of the control. The treatments of $AFB_2\;AFG_1,\;and\;AFG_2$ showed an inconsistent pattern in the formation of 8-OxodG in the liver of rats with increasing time. The expression of ras oncogene in the liver by $AFB_1$ at the dose of $1250\;{\mu}g/kg$ was increased twice compared to the control. The treatments of $AFB_2\;AFG_1,\;and\;AFG_2$ at all doses decreased the expression of ras in the liver. These results in the present study indicate that $AFB_1$ among aflatoxins with low comparable levels is the most toxic as determined by early biomarkers such as 8-OxodG formation and ras expression. However, the levels of 8-OxodG and ras as biomarkers were not useful to predict the relative hepatocarcinogenicity of aflatoxins to $AFB_1$ in the present model. Further studies are required to look for other biomarkers to predict carcinogenic potency of aflatoxins.

• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.236-243
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• 2006

Microarray analysis of gene expression has become a powerful approach for exploring the biological effects of drugs, particularly at the stage of toxicology and safety assessment. Acetaminophen (APAP) has been known to induce necrosis in liver, but the molecular mechanism involved has not been fully understood. In this study, we investigated gene expression changes of APAP using microarray technology. APAP was orally administered with a single dose of 50 mg/kg or 500 mg/kg into ICR mice and the animals were sacrificed at 6, 24 and 72 h of APAP administration. Serum biochemical markers for liver toxicity were measured to estimate the maximal toxic time and hepatic gene expression was assessed using high-density oligonucleotide microarrays capable of determining the expression profile of >30,000 well-substantiated mouse genes. Significant alterations in gene expression were noted in the liver of APAP-administered mice. The most notable changes in APAP-administered mice were the expression of genes involved in apoptosis, cell cycle, and calcium signaling pathway, cystein metabolism, glutatione metabolism, and MAPK pathway. The majority of the genes upregulated included insulin-like growth factor binding protein 1, heme oxygenase 1, metallothionein 1, S100 calcium binding protein, caspase 4, and P21. The upregulation of apoptosis and cell cycle-related genes were paralleled to response to APAP. Most of the affected gene expressions were returned to control levels after 72 hr. In conclusion, we identified potential hepatotoxicity makers, and these expressions profiling lead to a better understanding of the molecular basis of APAP-induced hapatotoxicity.