Hepatic Lipid Peroxidation Levels Research Articles

Suppressive effect of kamebakaurin on acetaminophen-induced hepatotoxicity by inhibiting lipid peroxidation and inflammatory response in mice.

Kamebakaurin (KA) is an ent-kaurane diterpenoid known to have anti-inflammatory potential. In the current study, we investigated whether pretreatment with KA could ameliorate acetaminophen (APAP)-induced hepatotoxicity by inhibiting the anti-inflammatory response in mice. Seven-week-old C57BL/6J mice were orally administered KA or olive oil emulsion for seven days. Twenty-four hours after the last KA or olive oil administration, the mice were intraperitoneally injected with 400mg/kg APAP or saline under feed deprived condition. The mice from each group were euthanized and bled for plasma analysis 24h after the injection. APAP increased plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), lipid peroxidation, and pro-inflammatory cytokines. Pretreatment with KA reduced the magnitude of APAP-induced increases in plasma levels of hepatic injury markers, lipid peroxidation, and inflammatory response. In addition, KA exhibited antioxidant capacity in a dose-dependent manner, with slight reactive oxygen species scavenging activity. Our results indicate that KA has the ability to protect the liver from APAP-induced hepatotoxicity, presumably by both inhibiting the inflammatory response and oxidative stress.

Olive oil bioactive compounds increase body weight, and improve gut health and integrity in gilthead sea bream (Sparus aurata).

An olive oil bioactive extract (OBE) rich in bioactive compounds like polyphenols, triterpenic acids, long-chain fatty alcohols, unsaturated hydrocarbons, tocopherols and sterols was tested (0, 0·08, 0·17, 0·42 and 0·73 % OBE) in diets fed to sea bream (Sparus aurata) (initial weight: 5·4 (sd 1·2) g) during a 90-d trial (four replicates). Fish fed diets containing 0·17 and 0·42 % OBE were 5 % heavier (61·1 (sd 1·6) and 60·3 (sd 1·1) g, respectively) than those of the control group (57·0 (sd 0·7) g), although feed conversion ratio and specific feed intake did not vary. There were no differences in lipid peroxidation (LPO) levels, catalase, glutathione reductase and glutathione S-transferase activities in the intestine and liver, although there was a tendency of lower intestinal and hepatic LPO levels in fish fed OBE diets. No differences in villus size were found among treatments, whereas goblet cell density in the control group was on average14·3 % lower than in fish fed OBE diets. The transcriptomic profiling of intestinal markers, covering different biological functions like (i) cell differentiation and proliferation, (ii) intestinal permeability, (iii) enterocyte mass and epithelial damage, (iv) IL and cytokines, (v) pathogen recognition receptors and (vi) mitochondria function, indicated that among the eighty-eight evaluated genes, twenty-nine were differentially expressed (0·17 % OBE diet), suggesting that the additive has the potential of improving the condition and defensive role of the intestine by enhancing the maturation of enterocytes, reducing oxidative stress, improving the integrity of the intestinal epithelium and enhancing the intestinal innate immune function, as gene expression data indicated.

Royal Jelly Supplementation Ameliorated Immune Impairment via Inhibition of Oxidative Stress in Low Micronutrient-induced Immunodeficient Mice

The effect of royal jelly (RJ) on the survival and immune dysfunctions of C57BL/6 mice induced by low micronutrient supplementation was investigated. Female C57BL/6 mice were supplemented with 0.2% or 1% royal jelly following induction of immune deficiency by 7.5% low micronutrient intake. The administration was maintained for 16 weeks for mortality assay and 10 weeks for the immunological analysis. Supplementation of 1% RJ was found to extend the median survival time in immune deficient mice. Although dysfunction of T- and B-cell mitogenesis was observed in primary cultured splenocytes during micronutrient deficiency, 1% RJ supplementation significantly increased T- and B-cell response against mitogens. In addition, 1% RJ supplementation partially recovered the abnormal alteration in cytokine secretion, indicated by the decreased secretion of T-helper 1 cytokines and increased secretion of T-helper 2 cytokines resulting from low micronutrient levels. The hepatic vitamin E level was significantly decreased (p<0.05) following micronutrient deficiency, in accordance with the increased hepatic lipid peroxidation level. However, 1% RJ supplementation reduced hepatic lipid peroxidation, which may result from the restoration of the hepatic vitamin E level. Therefore, the present study indicated that 1% RJ supplementation may ameliorate the premature mortality in mice through the restoration of immune dysfunctions, which may result from antioxidative ability of RJ in immune deficient mice caused by low micronutrient intake.

Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice.

Chronic excessive alcohol consumption (more than 40–80 g/day for males and more than 20–40 g/day for females) could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG) contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT), aspartate transaminase (AST), hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

Erratum: Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice.

[This corrects the article on p. 386 in vol. 10, PMID: 27478544.].

Chronotoxicity of bromobenzene-induced hepatic injury in mice.

The aim of the present study is to investigate whether or not bromobenzene (BB) toxicity varies with circadian periodicity. Seven-week-old male ICR mice were injected with 900 mg/kg (5.73 mmol/kg) BB intraperitoneally at 4 different time points of a day (zeitgeber time [ZT]: ZT0, ZT6, ZT12, and ZT18). Mortality was then monitored for 7 days after injection. Interestingly, mice were sensitive to BB acute toxicity at ZT6 while tolerant at ZT18. Moreover, in mice that were given a non-lethal dose of BB (540 mg (3.44 mmol)/kg), levels of alanine aminotransferase and aspartate aminotransferase, used as markers of hepatic injury, markedly increased in response to injection at ZT6, but did not increase significantly in response to injection at ZT18. In contrast, the markers of renal injury (creatinine and blood urea nitrogen), showed no significant difference in response to the two injection times. To further investigate this extreme circadian variation, we examined hepatic and renal lipid peroxidation levels, and conducted histopathological studies. Similar to our observation with alanine aminotransferase and creatinine, hepatic lipid peroxidation and histopathological changes were more pronounced than renal changes, and showed circadian variation. Our present investigation demonstrated that BB-induced mortality had clear circadian variation, and suggested that hepatic injury was one of the important factors for determination of this variation.

Compound 48/80, a mast cell degranulator, causes oxidative damage by enhancing vitamin C synthesis via reduced glutathione depletion and lipid peroxidation through neutrophil infiltration in rat livers.

In this study, we examined whether compound 48/80 (C48/80), a mast cell degranulator, causes hepatic oxidative damage in rats. Serum and liver biochemical parameters were determined 0.5, 3 or 6 h after a single treatment with C48/80 (0.75 mg/kg). Serum histamine and serotonin levels increased 0.5 h after C48/80 treatment but diminished thereafter. Increases in serum vitamin C (VC) and transaminases and hepatic hydrogen peroxide, lipid peroxide, and myeloperoxidase levels and a decrease in hepatic reduced glutathione level occurred 0.5 h after C48/80 treatment and further proceeded at 3 h, but these changes diminished at 6 h. Serum lipid peroxide and hepatic VC levels increased 3 h after C48/80 treatment. Hepatic glycogen level decreased 0.5 h after C48/80 treatment and further decreased at 3 h. Pre-administered ketotifen diminished all these changes found at 3 h after treatment, while pre-administered NPC 14686 diminished these changes except changes in serum histamine and serotonin levels. Hepatocellular apoptosis observed at 3 h after C48/80 treatment was attenuated by pre-administered ketotifen and NPC 14686. These results indicate that C48/80 causes oxidative damage by enhancing VC synthesis via reduced glutathione depletion-dependent glycogenolysis and lipid peroxidation through neutrophil infiltration following mast cell degranulation in rat livers.

Hepatoprotective activity of Macrothelypteris torresiana (Gaudich.) aerial parts against CCl4-induced hepatotoxicity in rodents and analysis of polyphenolic compounds by HPTLC

Macrothelypteris torresiana is a fern species belonging to family Thelypteridaceae. The present study was conducted to evaluate hepatoprotective potential of ethanol extract from M. torresiana aerial parts (EEMTAP) and detect the polyphenolic compounds present in the extract using high performance thin layer chromatography (HPTLC). Hepatoprotective potential of EEMTAP were tested at doses of 300 and 600mg/kg, per os (p.o.), on Wistar albino rats. The extract and silymarin treated animal groups showed significant decrease in activities of different biochemical parameters like serum glutamic oxaloacetic transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), alkaline phosphatase (ALP), which were elevated by carbon tetrachloride (CCl4) intoxication. The levels of total bilirubin and total protein alongwith the liver weight were also restored to normalcy by EEMTAP and silymarin treatment. After CCl4 administration the level of hepatic antioxidant enzymes such as Glutathione (GSH) and Catalase (CAT) were decreased whereas the level of hepatic lipid peroxidation (LPO) was elevated. The level of these hepatic antioxidant enzymes were also brought to normalcy by EEMTAP and silymarin treatment. Histological studies supported the biochemical findings and treatment with EEMTAP at doses 300 and 600mg/kg, p.o. was found to be effective in restoring CCl4-induced hepatotoxicity in rats. A simple HPTLC analysis was conducted for the detection of polyphenolic compounds in EEMTAP, and the result revealed the presence of caffeic acid as phenolic acid and quercetin as flavonoid. The proposed HPTLC method is simple, concise and provides a good resolution of caffeic acid and quercetin from other constituents present in EEMTAP.

Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity

Umbelliferone (UMB) is a coumarin derivative with promising hepatoprotective effects. In this study, we examined the possible protective effects of UMB against cyclophosphamide (CP)-induced hepatotoxicity, addressing the question of the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were orally administered UMB at doses 50 and 100mg/kg two weeks prior to CP injection. Five days after CP administration, the rats were sacrificed and samples were collected for analyses. CP induced a significant increase in circulating liver marker enzymes and pro-inflammatory cytokines. Hepatic lipid peroxidation and nitric oxide levels, and nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) expression were significantly increased following CP administration. UMB supplementation attenuated CP-induced inflammation and oxidative stress as assessed by restoration of the activity and expression of the antioxidant defenses, and suppression of pro-inflammatory cytokines. Histological examination also showed that UMB could significantly reduce CP-induced alterations. CP-induced rats showed significant down-regulation of Nrf2, HO-1 and PPARγ, an effect that was markedly reversed by UMB. In conclusion, the hepatoprotective effects of UMB appear to depend on co-activation of PPARγ and Nrf2, and subsequent suppression of oxidative stress and inflammation.

Saponins from the roots of Platycodon grandiflorum ameliorate high fat diet-induced non-alcoholic steatohepatitis

Platycodon grandiflorum has been healthy effects due to its various nutritious compounds and is considered as a functional food. Platycodon grandiflorum root-derived saponins (CKS) have been reported to show a variety of effects including anti-inflammatory and anti-oxidative activity. Although CKS have been studied on various bioactivities, the inhibitory effect of CKS on non-alcoholic steatohepatitis (NASH) is not examined. In this study, the inhibitory effects on HFD-induced NASH by CKS were determined. CKS suppressed HFD-induced hepatic lipid peroxidation level, collagen deposition, pro-fibrogenic and pro-inflammatory cytokines expression. CKS treatment suppressed HFD-induced COX-2 expression via inhibition of NF-κB p65 nuclear translocation and IκBα degradation. CKS treatment restored HFD-reduced Nrf2-mediated antioxidant enzymes expression. Furthermore, CKS treatment reinstated HFD-reduced peroxisomal proliferator-activated receptor alpha (PPARα)-regulated acyl-coA oxidase and carnitine-palmitoyl-coA transferase-1 expression. These findings suggest that CKS reduces HFD-induced NASH by up-regulation of Nrf2-mediated anti-oxidant enzymes and PPARα-regulated fatty acid oxidation.

Iron(III) diacetylmonoxime‐2‐hydrazinopyridine complex: A new prospective antitumor drug

Because of the side effects and drug resistance of cisplatin, a basic clinically approved chemotherapeutic drug, a new attempt is reported to develop a novel antitumor drug based on complexation of iron metal ion with organic moiety that may be effective and safer. A newly synthesized iron(III) diacetylmonoxime‐2‐hydrazinopyridine complex was tested firstly for its cytotoxicity and superoxide dismutase (SOD)‐mimic activity in vitro then for its antitumor activity against Ehrlich ascites carcinoma (EAC) and the related biochemical alterations in vivo in comparison with cisplatin. The complex showed 80.88% SOD‐mimic activity and IC50 of 2.6 μg ml−1. In EAC‐bearing mice, in a dose‐dependent manner, Fe(III) complex treatment exhibited significant hematological profile improvements, tumor volume, viable cell count and hepatic lipid peroxidation level decreases, life span extension, hepatic glutathione and total antioxidant capacity levels enhancements, hepatic SOD and catalase activities augmentations, liver function tests alterations attenuations, and hepatocyte nucleic acids content normalization. Thus, the Fe(III) diacetylmonoxime‐2‐hydrazinopyridine complex is a novel, promising, less toxic antitumor agent. Its killing of tumor cells may be via a reactive oxygen species scavenging mechanism.

Synergistic Protective Activity of Deuterium Depleted Water (DDW) and Satureja rechingeri Essential Oil on Hepatic Oxidative Injuries Induced by Acetaminophen in Rats

Studies presented in this paper report the synergistic protective activities of deuterium depleted water (DDW) with and without Satureja rechingeri oil mixture on acetaminophen induced hepatotoxicity in vivo model. The animals were divided into 6 groups (n = 5): The negative control group, the control group received acetaminophen dissolved in DMSO. The treatment groups received only DDW (30 and 60 ppm) concomitant with S. rechingeri oil following acetaminophen. In following, hepatic lipid peroxidation (LP), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), as well as ferric reducing ability of plasma (FRAP), aspartate transaminase (AST), alkaline phosphatase (ALP), alanine transaminase (ALT) and total bilirubin were estimated at 4, 8, 16 and 24 h after acetaminophen treatment. Acetaminophen caused seriously liver damage as noted by significant decrease activities of serum GPx, GR and SOD as well as the GSH content. Also, it resulted in a remarkably elevation of FRAP and LP levels and AST activity. The data indicated the hepatoprotective activity of DDW and DDW + E.O against acetaminophen induced toxicity by significantly depletion levels of hepatic LP and AST followed by elevation levels of the GSH and antioxidant enzymes (SOD, GPx and GR) after administration of acetaminophen. Indeed, these results are in agreement with decreased ACF formations in histopathological biopsies in the treatment groups. Therefore, it was concluded from the current results that DDW alone and in combination with E.O provided a synergistic effects in prevention of acetaminophen induced hepatotoxicity in rat. This protection may involve the reduction of oxidative stresses.

Lablab Purpureus Seeds Disrupt Hepatic and Renal Antioxidant Status in Male Rats

Abstract Nutrition constitutes an essential aspect of health care in both humans and other animals. Despite the numerous studies conducted on Lablab purpureus seeds, there is a paucity of information on its effects on hepatic and renal antioxidant status. The present study investigated the influence of three varieties of Lablab purpureus seeds (Rongai Brown, Rongai White and Highworth Black) on hepatorenal antioxidant status in male Wistar rats. Group I (control) rats were fed with the standard rat chow for 14 days while Groups II, III and IV rats were separately fed with feed containing the Rongai Brown, Rongai White and Highworth Black for 14 days, respectively. Lablab purpureus caused a significant decrease in renal superoxide dismutase (SOD) but increased hepatic SOD activity along with increased catalase, glutathione- S-transferase and glutathione peroxidase activities in both liver and renal tissues when compared with the control. Moreover, there was a significant decrease in the hepatic glutathione (GSH) level with concomitant elevation in hepatic and renal hydrogen peroxide and lipid peroxidation levels in all Lablab purpureus-fed rats. Lablab purpureus-fed rats demonstrated significant elevations in serum marker enzymes, aspartate aminotransferase and alkaline phosphatase along with increases in urea and creatinine levels. Histopathologically, kidney sections revealed normal renal architecture, whereas treatment-related lesions were identified in the liver of Lablab purpureus-fed rats. This study concluded that consumption of raw Lablab purpureus seeds induced hepatorenal toxicity in rats via the induction of oxidative stress.

Effect of tiron on remote organ injury in rats with severe acute pancreatitis induced by L-arginine.

Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas that can be complicated by involvement of other remote organs. Oxidative stress is known to have a crucial role in the development of pancreatic acinar damage and one of the main causes in multisystem organ failure in experimental AP. The aim of the study was to determine the effect of tiron on pancreas and remote organ damage in L-arginine (L-Arg) induced AP rat model. Thirty-two male rats were divided in random into four groups: control, tiron, L-Arg, and tiron with L-Arg. At the end of the experiment, blood samples were withdrawn for biochemical analysis. The pancreas, lung, kidney, and liver were collected for histopathological examination. Estimation of pancreatic water content was done. Analysis of pulmonary, hepatic, renal, and pancreatic lipid peroxide levels (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were carried out. Finally, nuclear factor kappa B (NF-κB) and transforming growth factor β1 (TGF-β1) expression in pancreatic tissue was determined. Results indicated that treatment with tiron significantly decreased lipid peroxide levels and markedly increased both SOD activity and GSH level. Moreover, histopathological analysis further confirmed that administration of tiron relatively ameliorates pancreatic acinar cells and remote organ damage. Increased immunoreactivity of NF-κB and TGF-β1 were reduced also by tiron treatment. These findings pointed out the protective role of the mitochondrial antioxidant, tiron against AP induced by L-Arg.

Hepatoprotective Effect of Wheat-Based Solid-State Fermented Antrodia cinnamomea in Carbon Tetrachloride-Induced Liver Injury in Rat.

Antrodia cinnamomea (A. cinnamomea) is an indigenous medical fungus in Taiwan and has multiple biological functions, including hepatoprotective and immune-modulatory effects. Currently, the commercially available A. cinnamomea are mainly liquid- and solid-state fermented A. cinnamomea. However, the hepatoprotective effect of solid-state fermented A. cinnamomea has never been reported. Here we evaluate the ability of air-dried, ground and non-extracted wheat-based solid-state fermented A. cinnamomea (WFAC) to protect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo. The results showed that oral administration of WFAC dose dependently (180, 540 and 1080 mg/kg) ameliorated the increase in plasma aspartate aminotransferase and alanine aminotransferase levels caused by chronic repeated CCl4 intoxication in rats. WFAC significantly reduced the CCl4-induced increase in hepatic lipid peroxidation levels and hydroxyproline contents, as well as reducing the spleen weight and water content of the liver. WFAC also restored the hepatic soluble protein synthesis and plasma albumin concentration in CCl4-intoxicated rats, but it did not affect the activities of superoxide dismutase, catalase, or glutathione peroxidase. In addition, a hepatic morphological analysis showed that the hepatic fibrosis and necrosis induced by CCl4 were significantly ameliorated by WFAC. Furthermore, the body weights of control rats and WFAC-administered rats were not significantly different, and no adverse effects were observed in WFAC-administered rats. These results indicate that WFAC is a nontoxic hepatoprotective agent against chronic CCl4-induced hepatic injury.

5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia–reperfusion injury in the mouse fatty liver model

BackgroundThe fatty liver could increase the risk of serious acute ischemia reperfusion (I/R) injury, and hepatic steatosis is indeed a major risk factor for hepatic failure after grafting a fatty liver. Materials & methodsFatty liver models of methionine- and choline-deficient high-fat mice were subjected to I/R injury with or without 5-aminolevulinic acid (5-ALA)/sodium ferrous citrate (SFC) treatment. Levels of hepatic enzymes, lipid peroxidation and apoptosis, inflammatory cytokines and heme oxygenase (HO)-1, and the carbon monoxide (CO) in the liver, and reactive oxygen species (ROS), inflammatory cytokines and members of the signaling pathway in isolated Kupffer were assessed. ResultsAlanine aminotransferase and aspartate aminotransferase levels, the number of necrotic areas, thiobarbituric acid reactive substance content, TUNEL-positive cells, infiltrated macrophages, and the inflammatory cytokine expression after I/R injury were dramatically decreased, whereas the endogenous CO concentrations and the HO-1 expression were significantly increased by 5-ALA/SFC treatment. The expression of toll-like receptors 2 and 4, NF-κB and inflammatory cytokines and ROS production in Kupffer cells were significantly decreased with 5-ALA/SFC treatment. Conclusion5-ALA/SFC significantly attenuates the injury level in the fatty liver after I/R injury.

Hepatoprotective effects of Nigella sativa seed extract against acetaminophen-induced oxidative stress.

To investigate the protective effects of Nigella sativa seed extract (NSSE) against acetaminophen (APAP)-induced hepatotoxicity in TIB-73 cells and rats. Toxicity in TIB-73 cells was induced with 10μmol/L APAP and the protective effects of NSSE were evaluated at 25, 50, 75, 100μg/mL. For invivo examination, a total of 30 rats were equally divided into five experimental groups; normal control (vehicle), APAP (800mg/kg body weight single IP injection) as a hepatotoxic control, and three APAP and NS pretreated (2 weeks) groups (APAP+NSSE 100mg; APAP+NSSE 300mg and APAP+NSSE 900mg/kg). TIB-73 cell viability was drastically decreased by (49.0±1.9)% after the 10μmol/LAPAP treatment, which also increased reactive oxygen species production. Co-treatment with NSSE at 25, 50, 75, and 100μg/mL significantly improved cell viability and suppressed reactive oxygen species generation. Invivo, the APAP induced alterations in blood lactate levels, pH, anionic gap, and ion levels (HCO3(-), Mg(2+) and K(+)), which tended to normalize with the NSSE pretreatment. The NSSE also significantly decreased elevated serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase induced by APAP, which correlated with decreased levels of hepatic lipid peroxidation (malondialdehyde), increased superoxide dismutase levels, and reduced glutathione concentrations. Improved hepatic histology was also found in the treatment groups other than APAP group. The invitro and invivo findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepatotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation.

Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice.

BACKGROUND/OBJECTIVESChanges in nutritional status during gestation and lactation have detrimental effects on offspring metabolism. Several animal studies have shown that maternal high-fat diet (HFD) can predispose the offspring to development of obesity and metabolic diseases, however the mechanisms underlying these transgenerational effects are poorly understood. Therefore, we examined the effect of maternal HFD consumption on metabolic phenotype and hepatic expression of involved genes in dams to determine whether any of these parameters were associated with the metabolic outcomes in the offspring.MATERIALS/METHODSFemale C57BL/6 mice were fed a low-fat diet (LFD: 10% calories from fat) or a high-fat diet (HFD: 45% calories from fat) for three weeks before mating, and during pregnancy and lactation. Dams and their male offspring were studied at weaning.RESULTSDams fed an HFD had significantly higher body and adipose tissue weights and higher serum triglyceride and cholesterol levels than dams fed an LFD. Hepatic lipid levels and mRNA levels of genes involved in lipid metabolism, including LXRα, SREBP-2, FXR, LDLR, and ABCG8 were significantly changed by maternal HFD intake. Significantly lower total liver DNA and protein contents were observed in dams fed an HFD, implicating the disturbed liver adaptation in the pregnancy-related metabolic demand. HFD feeding also induced significant oxidative stress in serum and liver of dams. Offspring of dams fed an HFD had significantly higher serum cholesterol levels, which were negatively correlated with liver weights of dams and positively correlated with hepatic lipid peroxide levels in dams.CONCLUSIONSMaternal HFD consumption induced metabolic dysfunction, including altered liver growth and oxidative stress in dams, which may contribute to the disturbed cholesterol homeostasis in the early life of male mice offspring.

Suppressive Effect of Kampo Formula “Juzen-taiho-to” on Carbon Tetrachloride-Induced Hepatotoxicity in Mice

The aim of the present study was to investigate whether pretreatment with the Japanese herbal medicine, "Juzen-taiho-to" (JTX), had an ameliorative effect on carbon tetrachloride (CCl4)-induced hepatotoxicity through anorexia prevention. Mice injected with CCl4 exhibited severe anorexia. Moreover, CCl4 increased the plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), lipid peroxidation, and hepatic Ca(2+) levels. Pretreatment with JTX recovered the CCl4-induced anorexia. In addition, JTX pretreatment decreased CCl4-induced plasma levels of hepatic injury markers. Increased Ca(2+) is a known indicator of the final progression to hepatocyte death, and CCl4-induced hepatotoxicity is mainly caused by oxidative stress. The present study indicated CCl4-induced lipid peroxidation and hepatic Ca(2+) content decreased with JTX pretreatment. Our results suggest that JTX has potential to protect of CCl4-induced anorexia, and the modulation of oxidative stress.

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury.

Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion.