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INTRODUCTION: Multiple sclerosis (MS) treatment options are primarily limited to immunomodulatory therapies in MS non-progressive forms. Nutrition intervention studies suggest that diet may be considered as a complementary treatment to control disease progression. Therefore, dietary intervention may help to improve wellness and ameliorate symptoms of MS patients. OBJECTIVES: To assess the effect of a low-fat diet with antioxidant supplementation on biochemical markers of institutionalized patients with progressive forms of multiple sclerosis. METHODS: A randomized prospective placebo-controlled study involving 9 participants, 5 of them assigned to the intervention group (low-fat diet and antioxidant supplementation) and the other 4 to the placebo group (low-fat diet). The effect of the dietary intervention, involving diet modification and antioxidant supplementation, was examined for 42 days by measuring anthropometric, biochemical parameters and oxidative stress markers in blood at baseline (day 0), intermediate (day 15) and end (day 42) stages of the treatment. RESULTS: The intervention group obtained C reactive protein levels significantly lower than those observed in the corresponding placebo group at the end of the study. Oxidative stress and inflammatory markers isoprostane 8-iso-PGF2[alpha] and interleukine IL-6 values also diminished after dietary intervention in the intervention group. Catalase activity increased significantly in the intervention group prior antioxidant supplementation. No significant differences were observed in other oxidative stress markers. CONCLUSIONS: The results suggest that diet and dietary supplements are involved in cell metabolism modulation and MS-related inflammatory processes. Consequently, low fat diets and antioxidant supplements may be used as complementary therapies for treatment of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. The pathological spectrum of NAFLD ranges from fatty liver to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Though NAFLD and NASH are becoming a major public health problem, ethical constraints on obtaining human liver tissue limit the interpretability of the data and the ability to delineate cause and effect from complex, interactive disease pathogenic pathways. Animal models of NASH can provide critical information leading to identify potential drug targets and to understand their molecular mechanisms, and are platforms for compound screening in drug development and for the assessment of novel therapeutic strategies. This review is aimed to offer an updated overview of the nutritional, genetic and pharmacologic animal models of NASH. Though the information derived from these models has clear relevance for the comprehension of the molecular basis of human disease, most of them fail to reproduce the full spectrum of liver pathology and the metabolic context that characterizes human NASH. Consequently, it is necessary to establish animal models that can best mimic the actual etiology, progression, and pathogenesis of the disease, and prove effectiveness for examining and selecting compounds with potential therapeutic benefit in NASH.

Flavonoids are a large class of naturally occurring compounds widely present in fruits, vegetables, and beverages derived from plants. Reports have suggested that these compounds might be useful for the prevention of a number of diseases, partly due to their anti-inflammatory properties. It has been demonstrated that flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, ciclooxygenase and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines or adhesion molecules. Modulation of the cascade of molecular events leading to the over-expression of those mediators include inhibition of transcription factors such as nuclear factor kappa B, activator protein 1, signal transducers and activators of transcription, CCAAT/enhancer binding protein and others. Effects on the binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen activated protein kinases. Although the numerous studies published with in vitro approaches allow identifying molecular mechanisms of flavonoid effects, the limited bioavailability of these molecules makes necessary validation in humans. Whatever the case, the data available make clear the potential utility of dietary flavonoids or new flavonoid-based agents for the possible treatment of inflammatory diseases. The present review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by flavonoids and the effects on cell signaling pathways responsible for their anti-inflammatory activity.

Dysregulation of apoptosis is a major contributor to the initiation and aggravation of liver injury. Agents that modulate apoptosis may be of therapeutic benefit in a number of liver diseases, and research related to cell type-specific activation or inhibition of apoptotic signaling pathways will provide new strategies for treatment.

Flavonoids are a group of natural substances that are located in sources of vegetal origin. More than 4,000 varieties of flavonoids have been identified. All of them are phenyl-benzopyrones of low molecular weight with a basic structure formed by two benzene rings united through a heterocyclic pyrane or pyrone. Besides their relevance in plants, flavonoids are important for human health. Their antioxidant capacity confers a therapeutic potential in cardiovascular diseases, gastric or duodenal ulcers, cancer or hepatic pathologies. Also important are their antiviral and anti-allergic actions, as well as their anti-thrombotic and anti-inflammatory properties. Prostaglandins and nitric oxide biosynthesis is involved in inflammation, and isoforms of inducible nitric oxide synthase (iNOS) and of cyclooxygenase (COX-2) are responsible for the production of a great amount of these mediators. It has been demonstrated that flavonoids are able to inhibit both enzymes, as well as other mediators of the inflammatory process such as reactive C protein or adhesion molecules. Modulation of the cascade of molecular events leading to the overexpression of those mediators include inhibition of transcription factors such as nuclear factor kappa B and AP-1, through the inhibition of protein kinases involved in signal transduction. Increased antioxidant defenses through activation of the NF-E2 related factor 2 (Nrf2) also contribute to the anti-inflammatory capacity of flavonoids.

Fulminant hepatic failure (FHF) is a very serious clinical sindrome that, in spite of the important therapeutical advances that have taken place in the last years by means of bioartifical hepatic support devices and hepatic transplantation, is still associated to a high mortality. Knowledge and treatment of the FHF have been limited by the lack of satisfactory animal models. Among the attempts to develop a suitable model are surgical models, such as hepatectomy and total and/or partial devascularization, or the use of chemical substances with hepatic toxicity, such as acetaminophen, azoximethane, galactosamine or thioacetamide, among others. However, most of these models do not adequatly reflect the pattern of the human disease and all of them present important limitations. Although viral hepatitis is one of the most frequent causes of FHF, the use of viral agents to develop animal models has been little and unfortunate. Our group has recently developed a viral animal model of FHF by means of the inoculation of rabbits with the virus of the rabbit hemorrhagic disease. This model displays biochemical, and histological characteristics, and clinical signs that ressemble those in human FHF. In the present article, the most widely used animal models of FHF, together with their main advantages and disadvantages, are presented.

Goals: The goal of this study is to assess the effect that supplementing parenteral diets with L-glutamine or with L-alanyl-L-glutamine has on the balance of oxidants/antioxidants in the liver and on detoxification systems mediated by P-450 cytochrome in rats., Material and Methods: Central catheters were inserted in the animals (n = 60) and they were randomly assigned to one of the following groups: a control group (C) with oral feeding and I.V. infusion of saline solution, a total parenteral nutrition group without glutamine (TPN without GLN), a parenteral nutrition group with glutamine supplement (TPN GLN), and a total parenteral nutrition group with a supplement of alanine-glutamine dipeptide (20 g/L) (TPN ALA-GLN). The parenteral nutrition provided was all isocaloric and isonitrogenated, and the infusions were administered at a speed of 2 ml/h over 5 days., Results: In the animals of the group without GLN, the liver concentration of glutathione was reduced while the levels of thiobarbituric acid reaction products (TBARS) increased. Supplementing with either glutamine or alanine-glutamine normalized the levels of glutathione but the TBARS levels only fell in the group with the dipeptide. This effect was parallel to the partial recovery of the antioxidant enzyme activities analyzed. The liver concentrations of P-450 cytochrome, P-450 cytochrome dependent mono-oxygenases and the clearance of antipyrine were not modified by the supplements of glutamine or alanine-glutamine., Conclusions: Our data suggest a greater protection by alanine-glutamine supplements against the injury produced by free radicals during TPN and the absence of any effect with either glutamine or alanine-glutamine supplements on the oxidative metabolism of the liver.

The aim of this study was to investigate the effects of cyclosporin (CyA) treatment on biliary glutathione efflux in rats of different ages (1, 2, 4, and 24 months). CyA treatment reduced the liver content of total glutathione in 1-, 2- and 24 month old rats (-30%, -43% and -30%, respectively). By contrast, oxidized glutathione (GSSG) concentration in liver tended to increase, although non significantly, in the rats aged 4 and 24 month (+36% and +28%, respectively). The oxidized-to-reduced glutathione ratio was significantly increased in 2-, 4- and 24 month old animals (+23%, +36% and >100%, respectively). Regarding biliary glutathione, our data indicate that efflux rates of total glutathione in control (untreated) rats increased to a maximum at 4 months, and decreased (-56%) in 24 month old rats, although values were still higher than those from young animals. CyA treatment significantly reduced biliary glutathione secretion except in 24 month old rats (-98%, -66% and -32%, at 1, 2 and 4 month, respectively). In addition, following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates into bile were significantly reduced by the drug only in 1- and 2 month old rats (-29% and -55%, respectively) and even tended to increase, although non significantly, in oldest animals. Our data indicate that inhibition of biliary glutathione efflux by CyA was greater in younger rats and support the view that increased intrabiliary catabolism of the tripeptide and inhibition of its canalicular transport could contribute to the decline in biliary glutathione secretion induced by the drug.

Flavonoids are phenolic compounds that represent substantial constituents of the non-energetic part of the human diet. They are naturally found in vegetables, berries, fruits, wine and beer. There are more than 5000 different flavonoids. The average intake depend on the country but the average intake is approximately 23 mg/day; quercetin is predominant at 16 mg/day. Flavonoids were considered initially to be substances without any benefit for humans. Later, it has been reported that they exert multiple biological effects due to their antioxidant and free radical-scavenging abilities. Although results from different studies have demonstrated that flavonoids can act as pro-oxidant at very high doses, most investigations have reported anti-inflammatory, antiviral, or anti-allergic effects and a protective role in heart diseases, cancer and different pathologies.

Free radicals are involved in aging and cyclosporin A-induced toxicity. The age-related changes in the liver oxidative status of glutathione, lipid peroxidation, and the activity of the enzymatic antioxidant defense system, as well as the influence of aging on the susceptibility to the hepatotoxic effects of cyclosporin (CyA) were investigated in rats of different ages (1, 2, 4, and 24 months). The hepatic content of reduced glutathione (GSH) increased with aging, peaked at 4 months, and decreased in senescent rats. By contrast, glutathione disulfide (GSSG) and thiobarbituric acid-reactive substances (TBARS) concentrations and superoxide dismutase, catalase, and glutathione peroxidase activities were higher in the oldest than in the youngest rats. CyA treatment, besides inducing the well-known cholestatic syndrome, increased liver GSSG and TBARS contents and the GSSG/GSH molar ratio, and altered the nonenzymatic and enzymatic antioxidant defense systems. The CyA-induced cholestasis and hepatic depletion of GSH, and the increases in the GSSG/GSH ratio, and in GSSG and TBARS concentrations were higher in the older than the mature rats. Moreover, superoxide dismutase and catalase activities were found to be significantly decreased only in treated senescent rats. The higher CyA-induced oxidative stress, lipoperoxidation, and decreases in the antioxidant defense systems in the aged animals render them more susceptible to the hepatotoxic effects of cyclosporin.

Background/aims: Our aim was to investigate whether the antioxidant quercetin might protect against liver injury in chronically biliary obstructed rats., Methods: Secondary biliary cirrhosis was induced by 28 days of bile duct obstruction. Animals received quercetin at 75, 150 and 300 micromol x kg body wt(-1) x day(-1) i.p. through the experimental period or at 150 micromol x kg body wt(-1) x day(-1) i.p. for the last 2 weeks., Results: Bile duct obstruction resulted in a decrease in the activities of antioxidant enzymes. Liver oxidised/reduced (GSSG/GSH) glutathione ratio, hepatic and mitochondrial thiobarbituric acid reactive substances (TBARS) and collagen content were significantly increased and a marked fibrosis and bile ductular proliferation was observed. Quercetin corrected the reduction in glutathione concentration and partially prevented the increase in collagen concentration, TBARS and GSSG/GSH ratio. Treatment resulted in a significant preservation of the activities of antioxidant enzymes, a less pronounced fibrosis and a marked inhibition of bile ductular proliferation. Maximal effects were reached with the intermediate quercetin dose given for 2 or 4 weeks., Conclusions: Quercetin reduces liver oxidative damage, ductular proliferation and fibrosis in biliary-obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction.

Background and Purpose: The aim of the study reported here was to investigate the pathomorphologic changes caused by experimentally induced dicroceliosis and their correlation with hepatobiliary function., Methods: Studies were carried out at days 80 and 120 after oral inoculation of hamsters with 40 metacercariae of Dicrocoelium dendriticum., Results: The parasite-induced pathologic changes were assessed by presence of fluke eggs in feces, increased plasma alanine transaminase and aspartate transaminase activities and morphologic alterations. Dicroceliosis was characterized by bile ductular proliferation and enlargement of the bile duct surface area caused by hyperplastic cholangitis in septal bile ducts. The liver from infected animals contained portal tracts infiltrated with small to moderate numbers of lymphocytes, macrophages, and eosinophils. Simultaneously, there was an increase in portal tract collagen that extended to the interlobular septa and caused pressure atrophy of the hepatic parenchyma. The concentration of thiobarbituric acid-reactive substances and the ratio of oxidized to reduced glutathione, measured as markers of oxidative stress, were significantly increased., Conclusions: The presence of oxidative alterations could be related to the morphologic evidence of chronic inflammatory response as well as to liver cellular injury indicated by cellular swelling, and increased presence of peroxisomes and lysosomes.

Our aim was to determine the effects of glutamine or alanyl glutamine parenteral supplementation on the liver oxidant/antioxidant balance and on cytochrome-P450-mediated detoxication in rats. Animals were infused for 5 d with standard total parenteral nutrition (TPN), glutamine-enriched TPN, or alanyl glutamine-enriched TPN. The hepatic concentration of glutathione was reduced, and the levels of thiobarbituric-acid-reactive substances (TBARS) were increased in animals receiving standard TPN. Both glutamine and alanyl glutamine supplementation normalized glutathione, but thiobarbituric-acid-reactive substance concentration was only decreased by ananyl glutamine. This effect was parallel to a partial recovery of the activity of antioxidant enzymes. Cytochrome-P450 liver content, cytochrome-P450-dependent monooxygenases, and antipyrine clearance were not modified by glutamine or alanyl glutamine. Our data suggest a better protection against free radicals by alanyl glutamine supplementation and an absence of effects of both glutamine and alanyl glutamine on liver oxidative metabolism.

The purpose of this investigation was to determine the effects of experimental dicrocoeliosis on bile formation in the hamster. Studies were carried out at 120 days after infection with an oral dose of 40 metacercariae of Dicrocoelium dendriticum. A significant elevation in bile flow (+20%) and in the biliary output of glutathione (+34%), bile acid (+59%), cholesterol (+108%), phospholipids (+99%) and alkaline phosphatase (+36%) was observed in the infected animals. The bile-to-plasma [14C] mannitol ratio increased to values greater than 1 and there was a reduced contribution (-26%) of biliary tree to bile formation. Those data suggest that enhancement in choleresis had a canalicular origin. The presence of oxidative stress, evidenced by the increased oxidized/reduced glutathione ratio and TBARS concentrations, may contribute to the elevated glutathione efflux into bile. Enhancement in bile acid output was not due to qualitative or quantitative changes in bile acid metabolism, as indicated by the absence of significant modification in liver cholesterol 7alpha-hydroxylase activity and bile acid profile in bile. Increase in the ability of the canalicular membrane to export bile acids was not involved, since maximal secretion rate for exogenously administered taurocholate was decreased. When bile flow, bile acid and biliary lipid secretion was determined in colchicine-pretreated animals differences between control and infected animals were abolished, suggesting that stimulation of the transcytotic vesicle pathway plays an important role in the alteration of the biliary function caused by dicrocoeliosis.

The purpose of this investigation was to determine the effects of experimental dicrocoeliosis on the hepatic oxidative drug-metabolizing system in hamsters. Studies were carried out 80 and 120 days after infestation with an oral dose of 40 metacercariae of Dicrocoelium dendriticum. The parasitic pathology was ascertained by detection of the fluke eggs in faeces, increased serum alanine aminotransferase and aspartate aminotransferase activities, and postmortem and histological findings. Cytochrome P-450 concentration, aniline hydroxylase activity and ethoxycoumarin O-deethylase activity were significantly decreased in both groups of infected animals. Aminopyrine N-demethylase activity and erythromycin N-demethylase activity were only reduced 120 days after infection. Effects on drug metabolizing enzymes were unrelated to changes in the physical state of the microsomal membrane, as assessed by measurement of fluorescence polarization. The results of this study indicate that the capacity of the liver for handling drugs and xenobiotics may be impaired as a consequence of dicrocoeliosis.

1. The structure of the Pirenaica, Verata, Guadarrama, Zamorana, Berciana, Granadina, Blanca Andaluza, Blanca Celtibérica, Murciana, Negra Serrana, Malagueña, Canaria, Palmera and Retinta goat breeds have been analysed. 2. Fourteen blood genetic systems were analysed: reduced glutathione (GSH), red cell potassium (Ke), haemoglobin (Hb), diaphorase (Dia), catalase (Ct), malate dehydrogenase (MDH), carbonic anhydrase (CA), X-protein (X), nucleoside phosphorylase (NP), alkaline phosphatase (Alp), amylase (Am), ceruloplasmin (Cp), transferrin (Tf) and albumin (Al). 3. Of the fourteen genetic systems studied, six were monomorphic (GSH, Ct, MDH, CA, NP and Cp) and eight polymorphic (Ke, Hb, Dia, X, Alp, Am, Tf and Al). Phenotypic and gene frequencies of the eight polymorphic genetic markers are reported.

The genetic distances separating 14 Spanish goat breeds are calculated from gene frequency data of 14 genetic blood markers (GSH, Ke, Hb, Dia, Ct, MDH, CA, X, NP, Alp, Am, Cp, Tf and Al). Working from the matrix of Nei's genetic distances we drew a dendrogram demonstrating a great genetic similarity among populations from Negra Serrana, Zamorana, Guadarrama, Retinta, Blanca Andaluza, Berciana and Pirenaica on one hand; and Canaria, Murciana, Blanca Celtibérica, Verata, Palmera, Malagueña and Granadina on the other. We discuss the similarities and differences within our classification using gene frequency data of the blood genetic markers studied, and classifications based chiefly on morphological and production data.