Vital members in the gut microbiotas altered by two probiotic Bifidobacterium strains against liver damage in rats.

BACKGROUND: Probiotics are effective to rectify the imbalanced gut microbiota in the diseased cohorts. Two Bifidobacterium strains (LI09 and LI10) were found to alleviate D-galactosamine-induced liver damage (LD) in rats in our previous work. A series of bioinformatic and statistical analyses were performed to determine the vital bacteria in the gut microbiotas altered by the LI09 or LI10 in rats. RESULTS: Two groups of representative phylotypes could distinguish the gut microbiotas of LI09 or LI10 groups from the other groups. Among them, OTU170_Porphyromonadaceae acted as a gatekeeper in LI09 group, while OTU12_Bacteroides was determined with multiple correlations in the gut network of LI10 group. Multiple reduced OTUs associated with LC and increased OTUs associated with health were determined in LI09 or LI10 groups, among which, increased OTU51_Barnesiella and reduced OTU99_Barnesiella could be associated with the protective effects of both the two probiotics. The gut microbiotas in LI09, LI10 and positive control groups were clustered into three clusters, i.e., Cluster_1_Microbiota, Cluster_2_Microbiota and Cluster_3_Microbiota, by Partition Around Medoids clustering analysis. Cluster_2_Microbiota was determined at least dysbiotic status due to its greatest LD dysbiosis ratio, lowest levels of liver function variables and plasma cytokines compared with the two other clustered microbiotas, suggesting the treated rats in Cluster_2 were at better health status. CONCLUSION: Our findings suggest that OTU170_Porphyromonadaceae and OTU12_Bacteroides are vital in the gut microbiotas altered by LI09 and LI10. Characteristics of the LD cohorts treated by LI09 or LI10 at different gut microbial colonization states could help monitor the cohorts' health status.

Role of Nutraceuticals in COVID-19 Mediated Liver Dysfunction.

COVID-19 is known as one of the deadliest pandemics of the century. The rapid spread of this deadly virus at incredible speed has stunned the planet and poses a challenge to global scientific and medical communities. Patients with COVID-19 are at an increased risk of co-morbidities associated with liver dysfunction and injury. Moreover, hepatotoxicity induced by antiviral therapy is gaining importance and is an area of great concern. Currently, alternatives therapies are being sought to mitigate hepatic damage, and there has been growing interest in the research on bioactive phytochemical agents (nutraceuticals) due to their versatility in health benefits reported in various epidemiological studies. Therefore, this review provides information and summarizes the juncture of antiviral, immunomodulatory, and hepatoprotective nutraceuticals that can be useful during the management of COVID-19.

Dietary Copper Reduces the Hepatotoxicity of (-)-Epigallocatechin-3-Gallate in Mice.

We developed Cu-deficient, -sufficient and -super nutrition mice models by feeding them with diet containing 1.68, 11.72 or 51.69 mg of Cu/kg for 28 days, respectively. Then, the mice were treated to (-)-epigallocatechin-3-gallate (EGCG, 750 mg/kg BW) by oral in order to assess the acute toxicity of the drug. Following EGCG treatment, the survival rates were 12.5%, 50% and 100% in the Cu-deficient, -sufficient and Cu-super nutrition groups of mice, respectively. Cu level and ceruloplasmin activity in serum were significantly increased with the increase of dietary Cu. However, the Cu supplementation did not produce any obvious impact on serum superoxide dismutase activity. Furthermore, ceruloplasmin, in vitro, significantly promotes EGCG oxidation accompanied with increasing oxidation products and decreasing levels of reactive oxygen species. These results, therefore, suggest that Cu can relieve EGCG hepatotoxicity, possibly by up-regulating ceruloplasmin activity, which can be used to promote EGCG applications.

Effect of apitherapy formulations against carbon tetrachloride-induced toxicity in Wistar rats after three weeks of treatment.

The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels) and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution). Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

Evaluation of turmeric extract on performance indices impressed by induced aflatoxicosis in broiler chickens.

The purpose of this study was evaluation of ethanolic turmeric extract (ETE; Curcuma longa) effect on overall performance including body weight (BW), body weight gain (BWG), feed intake and feed conversion ratio (FCR) weekly and cumulative for a period of 4 weeks with 300 commercial broiler chicks (Ross strain). These chicks were randomly divided into four groups with three replicates of 15 chicks in each replicate. In group A, chickens were fed a basal diet, in group B, chickens were fed a basal diet plus 3 ppm productive aflatoxin. In group C, chickens consumed a basal diet plus 0.05% ETE and in group D, chickens received a basal diet with 0.05% ETE plus 3 ppm productive aflatoxin. Aflatoxin production by Aspergillus parasiticus (PTTC NO:1850) in maize was according to the Shotwell method. The results revealed that there were no significant differences in BW, BWG and FCR between groups fed turmeric at 0.05% and the control group. The supplement of ETE in a diet containing 3 ppm aflatoxin can significantly improve performance indices compared with the group that consumed aflatoxin alone. In conclusion, our results suggest that turmeric extract (Curcuma longa) can provide protection against the negative effects of aflatoxin on performance of broiler chickens.

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.

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.

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.

Simultaneous Amelioratation of Colitis and Liver Injury in Mice by Bifidobacterium longum LC67 and Lactobacillus plantarum LC27.

Disturbances in the gut microbiota composition are associated with chronic inflammatory diseases of the intestine and the liver. In a preliminary study, Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 could inhibit Escherichia coli growth and lipopolysaccharide-induced NF-κB activation linked to gut inflammation. Here, we investigated their effects on 2,4,6-trinitrobenzesulfonic acid (TNBS)-induced colitis and liver damage in mice. First, oral administration of LC27 or LC67 (1 × 109 CFU/mouse) inhibited TNBS-induced colon shortening [F(5,30) = 100.66, P < 0.05] and myeloperoxidase activity [F(5,30) = 56.48, P < 0.05]. These probiotics restored TNBS-induced disturbance of gut microbiota, leading to the suppression of Proteobacteria to Bacteroidetes ratio and fecal and blood lipopolysaccharide levels. Second, LC27 and LC67 inhibited TNBS-induced NF-κB activation, reversed TNBS-suppressed tight junction protein expression, and restored Th17/Treg balance. Also, treatment with LC27 or LC67 significantly decreased TNBS-induced alanine transaminase [ALT, F(5,30) = 3.50, P < 0.05] and aspartate transaminase [AST, F(5,30) = 12.81, P < 0.05] levels in the blood, as well as t-butylhydroperoxide-induced ALT and AST levels. Finally, the mixture of LC27 and LC67 (0.5 × 109 CFU/mouse, respectively) synergistically attenuated TNBS- or t-butylhydroperoxide-induced colitis and liver damage. The capability of LC27 and LC67 to reverse TNBS-mediated microbiota shift and damage signals suggests that these probiotics may synergistically attenuate colitis and liver injury by alleviating gut microbiota imbalance.

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.

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.

Saccharomyces boulardii Administration Changes Gut Microbiota and Attenuates D-Galactosamine-Induced Liver Injury.

Growing evidence has shown that gut microbiome is a key factor involved in liver health. Therefore, gut microbiota modulation with probiotic bacteria, such as Saccharomyces boulardii, constitutes a promising therapy for hepatosis. In this study, we aimed to investigate the protective effects of S. boulardii on D-Galactosamine-induced liver injury in mice. Liver function test and histopathological analysis both suggested that the liver injury can be effectively attenuated by S. boulardii administration. In the meantime, S. boulardii induced dramatic changes in the gut microbial composition. At the phylum level, we found that S. boulardii significantly increased in the relative abundance of Bacteroidetes, and decreased the relative abundance of Firmicutes and Proteobacteria, which may explain the hepatic protective effects of S. boulardii. Taken together, our results demonstrated that S. boulardii administration could change the gut microbiota in mice and alleviate acute liver failure, indicating a potential protective and therapeutic role of S. boulardii.

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.

Influence of various diet regimens on deterioration of hepatic function and hematological parameters following carbon tetrachloride: a potential protective role of natural honey.

The objective was to assess the effects of commercial regular diet as control, total food restriction with honey, commercial regular diet with dextrose, or total food restriction with dextrose, on blood variables after carbon tetrachloride (CCl4) administration. Sprague Dawley albino rats were divided into four groups, 10 rats each; Group 1 rats were on commercial regular diet, Group 2 rats were on commercial regular diet with 50% dextrose, Group 3 rats were on total food restriction with 50% dextrose, and Group 4 rats were on total food restriction with 50% honey. Rats in all the groups were i.m. administered CCL4 (2.4 mL kg b. wt.-1). Blood tests including ALT, AST, serum albumin, serum protein, BUN, blood glucose (BG), hemoglobin (Hb), and white blood cell (WBC) were performed before CCl4 administration and repeated after 48 and 96 h of post-injection. In Group 1, CCl4 caused significant elevation in AST and ALT, and decrease in BS, WBC, and BUN; lower elevation in AST and ALT at 48 h and decreased AST and ALT at 96 h were obtained when dextrose was added to commercial regular diet (Group 2). Using dextrose alone (Group 3), though there was significant elevation of AST and ALT and decrease in BUN and WBC as compared to baseline values, significant decrease in ALT, AST, and BUN as compared to control was obtained. During absolute honey feeding (Group 4), elevation in AST and ALT obtained, following CCl4 administration was significantly less than the values obtained in all other groups; with lower elevation in AST and ALT as compared to baseline values. Honey increased serum albumin, serum protein, BG, and caused lower reduction in Hb. Conclusively, exclusive honey feeding (50% concentration) significantly modifies and ameliorates biochemical and hematological changes obtained after CCl4 injection.

Protective effect of Punica granatum peel and Vitis vinifera seeds on DEN-induced oxidative stress and hepatocellular damage in rats.

This study was designed to find out the efficacy of ethanol extracts of Punica granatum peel and Vitis vinifera seeds on diethylnitrosamine (DEN)-induced oxidative stress and hepatocellular damage in Wistar rats. Rats were divided into four groups. The first group served as normal control, and the second group received DEN at a dose of 200 mg/kg body weight by single intraperitoneal administration. The third one received DEN as in DEN-treated group and co-treated with 400 mg/kg P. granatum peel extract. The final group also received DEN and co-treated with 400 mg/kg V. vinifera seed extract. DEN administration to rats resulted in significantly elevated levels of serum SGPT, SGOT, ALP, and GGT which is indicative of hepatocellular damage. DEN-induced oxidative stress was confirmed by elevated levels of lipid peroxides and decreased activities of superoxide dismutase, catalase, and glutathione peroxidase in the serum and liver tissues. The status of non-enzymatic antioxidants like vitamin C, vitamin E, and reduced glutathione were also found to be decreased in serum and tissues of DEN-administered rats. Co-treatment with the P. granatum peel and V. vinifera seed extracts orally for 12 weeks significantly reversed the DEN-induced alterations in the serum and liver tissues.

Mechanisms of increased liver tissue repair and survival in diet-restricted rats treated with equitoxic doses of thioacetamide.

Moderate dietary or caloric restriction (DR) modulates animal physiology in a beneficial fashion. Previously, we have reported an equitoxic dose experiment where liver injury in DR male Sprague-Dawley rats exposed to a low dose of thioacetamide (TA, 50 mg/kg) was similar to that observed in ad libitum fed (AL) rats exposed to a 12-fold higher dose (600 mg/kg). Paradoxically, the AL rats experienced 90% mortality while all of the DR rats, with the same amount of initial bioactivation-mediated liver injury, survived. The protection observed in the DR rats was due to efficient compensatory liver tissue repair, which was delayed and attenuated in the AL rats, leading to progression of liver injury. The objective of the present study was to investigate the molecular mechanisms of the enhanced tissue repair in the DR rats upon equitoxic challenge with TA. Promitogenic mechanisms and mediators such as proinflammatory cytokines (TNF-alpha and IL-6), growth factors (TGF-alpha and HGF), and inducible nitric oxide synthase (iNOS) were estimated over a time course after equitoxic challenge (50 mg/kg to DR vs. 600 mg/kg to AL rats). Except for TNF-alpha, all other molecules were expressed earlier and in greater amount in the DR rats. IL-6 was 10-fold greater and peaked 12 h earlier; HGF also peaked 12 h sooner in the DR rats, when it was 2.5-fold greater than the value in the AL rats. TGF-alpha expression in livers of DR rats increased after TA administration and peaked at 24 h. In the AL rats, it was lower and peaked at 36 h. Diet restriction alone induced iNOS 2-fold in the DR rats and remained elevated until 12 h after TA administration, then declined thereafter. The lower iNOS activity in the AL rats further decreased after TA injection. DR rats exhibited higher apoptosis after thioacetamide administration, which further increased the efficiency of tissue repair. Taken together, these data indicate that even though the liver injury is near equal in AL and DR rats, sluggish signal transduction leads to delayed liver regeneration, progression of liver injury, and death in the AL rats. The equitoxic dose experiment indicates that stimulation of tissue repair is independent of the extent of initial liver injury and is governed by physiology of diet restriction. DR stimulates promitogenic signaling leading to a quick and timely response upon liver injury, arrest of progressive injury on one hand, and recovery from injury on the other, paving the way for survival of the DR rats.

[Possibility of using the urea increment index for assessing the anabolic effectiveness of parenteral nitrogen feeding in toxic hepatitis]. / Vozmozhnost' ispol'zovaniia pokazatelia inkrementa mocheviny dlia otsenki anabolicheskoi éffektivnosti azotistogo parenteral'nogo pitaniia pri toksicheskom gepatite.

To determine the anabolic effectiveness of nitrous preparations for the parenteral alimentation an urea increment rate in normal albino rats and in the ones with parenchymatous hepatitis was used. With subcutaneous introduction of nitrous preparations moriamine S-2, aminosol, polyamine and of an improved caseine hydrolysate the level of the blood urea was found to attain the maximum in 6 hours. With toxic lesion of the liver the ureogenic function remains intact and, for this reason, this test may be used for assessing the anabolic effectiveness of the preparations with a changed functional state of the liver in different pathological conditions. The urea increment rate may be recommended for determining the biological value of the preparations for nitrogenous parenteral alimentation.

[Influence of qualitatively different diets on the reproductive capacity and function of the adrenal cortex in rats with experimental toxic hepatitis]. / Vliianie kachestvenno razlichnogo pitaniia na reproduktivnuiu sposobnost' i funktsiiu kory nadpochechnikov u krys pri éksperimental'nom toksicheskom gepatite

The effect of a diet rich in protein and the group B vitamins on the function of the ovaries and adrenal cortex, as well as on the reproductive capacity of animals with experimental affection of the liver produced by administration of carbon tetrachloride was studied on 115 mongrel albino female-rats. A high-standard semisynthetic diet devised at the Institute of nutrition of the AMS of the USSR and three isocaloric experimental diets calorifically enriched by 20, 50 and 100 per cent and containing a double amount of the group B vitamins were used in tests. The protein and vitamins enrichment of the diet, although failing to normalize the estrual cycle, neveretheless contributed to a significant reduction of the embryos' death in pregnant animals, the restoration of the reproductive capacity of the rats being directly proportional to the degree of the protein enrichment of the diet. The use of experimental diets helped normalize the adrenal cortex function in pregnant rats with toxic hepatitis, this manifesting itself in the falling amount of corticosterone in the blood serum outflowing from the suprarenals down to the control level.

[Effectiveness of dietary non-starch polysaccharides in experimental toxic hepatitis]. / Effektivnost' pishchevykh nekrakhmal'nykh polisakharidov pri éksperimental'nom toksicheskom gepatite.

The efficiency of some polysaccharides was investigated in mice with an experimental toxic hepatitis. Hepatitis was induced by the oral administration of 10% solution CCl4 in olive oil at a dosage of 3 ml/kg body weight every day during 7 days. After that tested substances were administrated every day 30-40 min before a feeding at a dosage of 150 mg/kg body weight during 14-21 days. Results showed that a calcium alginate, two low-methoxyl pectins (one with the degree of esterification about 50% and other with the degree of esterification less 5%), fucoidan, and chitozan, but not lambda-carrageenan and kappa-carrageenan, have beneficial affects on liver total lipid, glycogen, malondialdehyde, and diene conjugates as well as on blood total lipid and alanine aminotransferase activity in animals with experimental toxic hepatitis.

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.