Dietary Trichosporon mycotoxinivoron modulates ochratoxin-A induced altered performance, hepatic and renal antioxidant capacity and tissue injury in broiler chickens.

Ochratoxin A (OTA), an important fungal metabolite in foods and feeds has been shown to induce oxidative stress and cellular injuries to human and animal subjects. This study was designed to investigate the mode of action of a biological modifier Trichosporon mycotoxinivorans (TM), against OTA-mediated oxidative stress and tissue toxicity on broiler chickens. The birds were offered diets supplemented with OTA (0.15 and 0.3 mg/kg feed) and/or TM (0.5, 1.0 g/kg) for 42 days of age, and blood and tissue samples were collected to examine the oxidative stress, biochemical and histopathological parameters. Dietary OTA at all the tested levels induced the hepatic and renal tissue injury as indicated by significant decreased total antioxidant capacity in these organs along with significant decreased (p ≤ 0.05) serum concentrations of total proteins and albumin. The serum concentrations of alanine aminotransferase (ALT) and urea were significantly increased, and these observations were further supported by degenerative changes and increased relative weights of liver and kidneys. The dietary supplementation of TM at both tested levels relieved the detrimental impact of 0.15 and 0.3 mg OTA/kg on the studied parameters. The results of the study demonstrated that dietary TM significantly protects broiler chickens by reducing OTA-induced oxidative damage and tissue injury.

Consumption of Goats' Milk Protects Mice From Carbon Tetrachloride-Induced Acute Hepatic Injury and Improves the Associated Gut Microbiota Imbalance.

Drugs used to treat liver diseases have serious side effects; it is important to search for safe functional foods with hepatoprotective functions and few side effects. In this study, potential hepatoprotective effects of goats' milk and cows' milk on mice with CCl4-induced acute hepatic injury were evaluated. We also elucidated the role of goats' and cows' milk on the regulation of CCl4-induced gut microbiota imbalance. In mice with liver damage induced by CCl4, administration of goats' milk for 7 days prior to injection of CCl4 had beneficial effects on the indicators of liver damage within 1 day: the area of liver necrosis was small; activity of alanine transaminase (ALT) and aspartate transaminase (AST) and expression of the genes CYP2E1 and TNF-α were lower than that of model group of mice. By 7 days after CCl4 injection, there were no significant differences in liver damage indicators (ALT, AST, malondialdehyde, superoxide dismutase, and glutathione) between the goats' milk group, which continued to receive goats' milk, and the untreated control group of mice showing that goats' milk continued to protect against liver damage. Throughout the entire experiment, the community of gut microbes from mice in the goats' milk treatment was more similar to the untreated control group than to the cows' milk group and the model group, indicating that intake of goats' milk prior and post-CCl4 injection effectively prevented and alleviated the intestinal microbial disorder that caused by CCl4 in mice. Our research suggests that goats' milk could be developed as a potential functional food to prevent/protect against liver injury.

Hepatoprotective Effects of the Honey of Apis cerana Fabricius on Bromobenzene-Induced Liver Damage in Mice.

Apis cerana honey (honey of Apis cerana Fabricius), widely distributed in the mountain areas of East Asia, has not been studied fully. The hepatoprotective activity of A. cerana honey was evaluated against bromobenzene-induced liver damage in mice. In high dose, A. cerana honey can significantly alleviate liver injury, as is indicated by the depressed levels of serum alanine aminotransferase (ALT) (59.13%) and aspartate aminotransferase (AST) (79.71%), the inhibited malondialdehyde (MDA) content (63.30%), the elevated activities of superoxide dismutase (SOD) (73.12%) and glutathione-Px (57.24%), and the decreased expression of Transforming growth factor ß1 (51.83%) induced by bromobenzene (P < 0.05). The quantitative analysis of twelve major constituents (1 to 12) of A. cerana honey was executed by high performance liquid chromatography-diode array detector. The results indicate that treatment with A. cerana honey can prevent bromobenzene-induced hepatic damage in mice. Polyphenols might be the bioactive substances attributed to its antioxidant properties and intervention of oxidative stress.

Caloric Restriction Prevents Carcinogen-Initiated Liver Tumorigenesis in Mice.

Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences oncogenesis, although its interactions with exercise and CR are not well understood. Therefore, to investigate the potential interactions between diet and lifestyle interventions on liver tumorigenesis, the carcinogen diethylnitrosamine was administered to 72 male C57Bl/6 mice that were subsequently fed diets enriched with lard (CTL) or olive oil and were further stratified to voluntary wheel running (Ex) or 30% CR for 49 weeks. Although Ex and diet composition did not influence liver oncogenesis, CR prevented hepatic tumor formation. In addition, CR reduced steatosis, hepatocyte ballooning, inflammation, and immune cell infiltration, all of which are hallmarks in the progression of nonalcoholic fatty liver disease to liver tumorigenesis. RNA sequencing of nontransformed liver tissues from CR mice revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. These data demonstrate that CR protects against steatosis, liver inflammation, and liver injury and is a robust deterrent of carcinogen-induced hepatic oncogenesis. Cancer Prev Res; 10(11); 660-70. ©2017 AACR.

Valproate-induced liver injury: modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen.

BACKGROUND: The polyunsaturated, ω-3 fatty acid, docosahexaenoic acid (DHA), claims diverse cytoprotective potentials, although via largely undefined triggers. Thus, we currently first tested the ability of DHA to ameliorate valproate (VPA)-evoked hepatotoxicity, to modulate its anticonvulsant effects, then sought the cellular and molecular basis of such actions. Lastly, we also verified whether DHA may kinetically alter plasma levels/clearance rate of VPA. METHODS AND RESULTS: VPA (500 mg/kg orally for 14 days in rats) evoked prominent hepatotoxicity that appeared as a marked rise (2- to 4-fold) in serum hepatic enzymes (γ-glutamyl transferase [γ-GT], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), increased hepatic lipid peroxide (LPO) and tumor necrosis factor-alpha (TNFα) levels, as well as myeloperoxidase (MPO) activity (3- to 5-fold), lowering of serum albumin (40 %), and depletion of liver reduced-glutathione (GSH, 35 %). Likewise, histopathologic examination revealed hepatocellular degeneration, replacement by inflammatory cells, focal pericentral necrosis, and micro/macrovesicular steatosis. Concurrent treatment with DHA (250 mg/kg) markedly blunted the elevated levels of liver enzymes, lipid peroxides, TNFα, and MPO activity, while raising serum albumin and hepatic GSH levels. DHA also alleviated most of the cytologic insults linked to VPA. Besides, in a pentylenetetrazole (PTZ) mouse convulsion model, DHA (250 mg/kg) markedly increased the latency in convulsion evoked by VPA, beyond their individual responses. Lastly, pharmacokinetic studies revealed that joint DHA administration did not alter serum VPA concentrations. CONCLUSIONS: DHA substantially ameliorated liver injury induced by VPA, while also markedly boosted its pharmacologic effects. DHA manipulated definite cellular machinery to curb liver oxidative stress and inflammation, without affecting VPA plasma levels. Collectively, these protective and synergy profiles for DHA propose a superior VPA-drug combination regimen.

Effect of Punica granatum (pomegranate) juice extract on healthy liver and hepatotoxicity induced by diethylnitrosamine and phenobarbital in male rats.

The effect of pomegranate juice (PJ) on hepatic antioxidant enzyme activities, lipid peroxidation, DNA fragmentation (DNAF), and caspase-3 activity in rats both treated and not treated with diethylnitrosamine (DEN) and phenobarbital (PB) was studied. Administration of rats with DEN and PB caused an elevation in the levels of malondialde-hyde (MDA), DNAF, and activities of glutathione reductase (GSR) and caspase-3, while the activities of superoxide dismutase, glutathione S-transferase, total glutathione peroxidase (t-GPx), and glutathione (GSH) level were decreased in hepatocytes compared to the control. Treatment of rats with PJ pre, during, and post DEN and PB administration improved liver function and decreased the levels of MDA, DNAF, t-GPx, GSR, and caspase-3 activities, but the GSH level did not change compared to the D-P group. This indicates that PJ reduced the oxidative stress and apoptosis induced by DEN and PB. Administration of healthy rats with PJ only for a long period induced oxidative stress and apoptosis for hepatocytes.

Dietary honey and ginseng protect against carbon tetrachloride-induced hepatonephrotoxicity in rats.

Liver diseases are amongst the most serious health problems in the world today and hepatocellular carcinoma is one of the world's deadliest cancers. The aim of the current study was to evaluate the protective effect of sider honey and/or Korean ginseng extract (KGE) against carbon tetrachloride (CCl(4))-induced hepato-nephrotoxicity in rat. Eighty male Sprague-Dawley (SD) rats were allocated into different groups and over a 4-week period, they orally received honey and/or KGE or were treated either with CCl(4) alone (100 mg/kg b.w) or with CCl(4) after a pretreatment period with honey, KGE or a combination of both. Clinical, clinico-pathological and histopathological evaluations were done and CCl(4)-treated groups were compared with rats receiving no treatment and with rats given honey, KGE or a combination of these substances. The results indicated that oral administration of CCl(4) induced severe hepatic and kidney injury associated with oxidative stress. The combined treatment with CCl(4) plus honey and/or KGE resulted in a significant improvement in all evaluated parameters. This improvement was prominent in the group receiving CCl(4) after combined pretreatment with honey and KGE. Animals receiving honey and/or KGE (without CCl(4)-treatment) were comparable to the control untreated group. It could be concluded that honey and KGE protect SD rats against the severe CCl(4)-induced hepatic and renal toxic effects. Our results suggest that the protective activity of honey and KGE may have been related to their antioxidant properties.

Mechanism of the suppression against D-galactosamine-induced hepatic injury by dietary amino acids in rats.

To elucidate the mechanism by which dietary amino acids suppress the D-galactosamine (D-GalN)-induced hepatitis, we examined the involvement of Kupffer cells, tumor necrosis factor-alpha (TNF-alpha) and apoptosis in the mechanism. In experiment 1, the rats were fed with 10% L-glutamine or 5% glycine diet injected with D-GalN with or without gadolinium chloride (GdCl3)-pretreatment. The results indicated that these amino acids suppressed the D-GalN-induced elevation of serum transaminase activities, irrespective of GdCl3-pretreatment. In experiment 2, rats were fed with 10% of L-glutamine, L-serine, L-alanine or L-glutamic acid diets injected with D-GalN. The results demonstrated that all these amino acids suppressed the D-GalN-induced elevation of serum transaminase activities, but that serum TNF-alpha concentrations and hepatic caspase-3 activities in the rats were not appreciably changed. In conclusion, the suppressive effects of amino acids on D-GalN-induced hepatitis were suggested not to be always mediated by the inhibition of Kupffer cells --> TNF-alpha --> apoptosis pathway.

The anti-fibrotic effect of green tea with a high catechin content in the galactosamine-injured rat liver.

Previously, we reported that the oral administration of green tea rich in catechins restored levels of several biomarkers increasing in galactosamine-treated rats to nearly control values. These biomarkers included serum transaminase activities, serum concentrations of tumor necrosis factor-alpha and interleukin 1-beta, and the hepatic mRNA expression of these inflammatory cytokines. In the present study, we examined possible anti-fibrotic effects of green tea in galactosamine-induced hepatitis. The results of the reverse transcription and polymerase chain reaction indicated that the increase in gene expression of the alpha1 chain of collagen type 1 and transforming growth factor beta-1 in the injured liver 24 h post-injection of galactosamine was suppressed by the administration of green tea. Masson's trichrome staining demonstrated that the extent of fibrogenesis after 14 days was greater in the galactosamine-injured livers not treated with green tea than the treated ones. These results suggest that the drinking of green tea with a high catechin content may help to prevent and/or attenuate the development of fibrosis in hepatitis.

Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration.

We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-kappaB (NF-kappaB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-alpha (TNF-alpha). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-kappaB, and mRNAs for Cox-2 and TNF-alpha. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-kappaB activation, and reduced expression of TNF-alpha and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-kappaB and reduced levels of TNF-alpha and Cox-2.