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We investigated the effect of two immunosuppressant drugs, FK506 and rapamycin, on reactive oxygen species (ROS) generation, nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression and nuclear factor kappa B (NF-κB) activation in lipopolysaccharide (LPS)-activated rat hepatocytes. Primary culture of rat hepatocytes was treated with LPS in the presence and absence of FK506 or rapamycin. LPS increased the release of lactate dehydrogenase (LDH) and nitrite into the culture medium. Western blot and reverse transcription–polymerase chain reaction analyses demonstrated increased levels of iNOS protein and mRNA. Both immunosuppressant agents inhibited the induction of iNOS mRNA and protein stimulated by LPS. ROS generation, assessed by flow cytometry using dichlorodihydrofluorescein diacetate, was significantly decreased by FK506 and rapamycin. Moreover, electrophoretic mobility shift assay experiments indicated that both drugs blocked the LPS-induced activation of NF-κB. Inhibitor kappa B protein levels were decreased by LPS and this effect was partly blocked by FK506 or rapamycin. In summary, both immunosuppressant agents decreased the intracellular generation of ROS and inhibited NO production and iNOS expression at mRNA level in association to NF-κB activation. In addition to its capacity to reduce acute allograft rejection, this study highlights the anti-inflammatory properties of FK506 and rapamycin. [Copyright &y& Elsevier]

Introduction: Inflammation is one of the main contributory factors to the etiopathogenesis of multiple sclerosis (MS). Dietary interventions with Lipia citriadora (lemon verbena) extracts have been proved to be effective in the prevention of inflammatory diseases. Objectives: The aim of this study is to evaluate the effect of lemon verbena supplementation in pro- and anti-inflammatory serum biomarkers of patients with different clinical subtypes of multiple sclerosis. Methods: The effect of lemon verbena supplementation (10% w/w verbascoside) was evaluated in a randomized, double-blinded placebo-controlled study with30 participants classified in relapsing-remitting (n=10), primary progressive (n=5) and secondary progressive (n=15) MS presentations. Serum cytokine and C reactive protein levels were assessed in intervention and control groups for each MS clinical subtype after 28 days of dietary supplementation. Results: Serum levels of C reactive protein and 8 cytokines/inflammatory (IFN-γ, IL-12, IL-23, IL-6, TNF-α,TGF-β, IL-4 and IL-10) markers were studied. Secondary progressive MS- supplemented patients showed C reactive protein concentrations significantly lower compared to the placebo group (p<0.005). IFN-γ levels decreased for all MS-treated groups whereas IL-12 diminished levels were observed for relapsing-remitting type (p<0.05). Anti-inflammatory cytokine concentrations ofIL-4 (difference 2.98 ± 2.99 pg/mL) and IL-10 (difference1.78 ± 5.54 pg/mL) increased in secondary progressive MS patients (p<0.05).Conclusion: The variation of several pro- and anti-inflammatory markers after supplementation suggests that lemon verbena extracts may affect cytokine profiles in multiple sclerosis. Further investigation on dietary components with antioxidant and anti-inflammatory properties may contribute to understand MS pathogenesis and ameliorate MS symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long‐term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg−1d−1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev‐erbα, and Rev‐erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia‐inducible factors Hif‐1α and Hif‐2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl‐2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin‐treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV‐ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro‐apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

The reason of higher number of citations of some articles is discussed. Some considerations about the journals' impact factor, its merits and its pitfalls are also made. Scientific journals' impact factor, popularized by the Institute for Scientific Information, has become an objective parameter for authors' evaluation and also for institutions and other related circumstances. There is no reason for the impact factor's gap between some English journals and those written in other languages. English journals probably benefit of the "Mathew's effect", according to which eminent scientists are more rewarded by similar contributions than others less known. It is paradoxical that most of the major achievements of our age do not appear among the 100 most cited articles. There is no homogeneity among all the articles appearing in each scientific journal: half of the articles are cited ten times more than the other half. However, those articles cited 0 times are credited like the better ones. Each article should be evaluated by its own citations, which would be its impact factor; the authors should be evaluated by their H index. [ABSTRACT FROM AUTHOR]

After 36 years of continued publication of the journal Nutrición Hospitalaria, a list with the ten most cited articles published in it is elaborated. The top ten most cited articles in the world literature and stratification according to language, English or Spanish, subject, or period of time published are also analyzed. Nutr Hosp is the most important Ibero latin American nutrition journal. Nutr Hosp published 369 items in 2014 gaining the fourth position among all the world's journals devoted to nutrition. Article publication in English, or simultaneously in Spanish and English and Open Access policy probably benefit the number of citations. [ABSTRACT FROM AUTHOR]

Liver fibrosis is scar tissue resulting from an uncontrolled wound-healing process in response to chronic liver injury. Liver damage generates an inflammatory reaction that activates hepatic stellate cells ( HSC) that transdifferentiate from quiescent cells that control retinol metabolism to proliferative and migratory myofibroblasts that produce excessive amounts of extracellular matrix proteins, in particular collagen 1a1 ( COL1 A1). Although liver fibrosis is reversible, no effective drug therapy is available to prevent or reverse HSC activation. Melatonin has potent hepatoprotective properties in a variety of acute and chronic liver injury models and suppresses liver fibrosis. However, it remains unclear whether melatonin acts indirectly or directly on HSC to prevent liver fibrosis. Here, we studied the effect of melatonin on culture-activated rat HSC. Melatonin dose-dependently suppressed the expression of HSC activation markers Col1a1 and alpha-smooth muscle actin ( α SMA, Acta2), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor-related orphan receptor-alpha ( ROR α/ Nr1f1) was expressed in quiescent and activated HSC, while the membranous melatonin receptors ( Mtrn1a and Mtrn1b) were not. The synthetic ROR α agonist SR1078 more potently suppressed Col1a1 and α Sma expression, HSC proliferation, and lipid droplet loss, while the ROR α antagonist SR1001 blocked the antifibrotic features of melatonin. Melatonin and SR1078 inhibited the expression of Alox5, encoding 5-lipoxygenase (5- LO). The pharmacological 5- LO inhibitor AA861 reduced Acta2 and Col1a1 expression in activated HSC. We conclude that melatonin directly suppresses HSC activation via ROR α-mediated inhibition of Alox5 expression, which provides novel drug targets to treat liver fibrosis. [ABSTRACT FROM AUTHOR]

In hepatic toxicity induced in rats by two injections of thioacetamide (TAA, 350 mg/kg with an interval of 8 hr), the action of quercetin was investigated. After 96 hr, TAA administration resulted in hepatic necrosis, significant increases in serum transaminase activity, and increases in hepatic lipoperoxidation. Thioacetamide-induced hepatotoxicity also showed changes in antioxidant enzymes in the liver of rats, with alterations in p-ERK 1/2 (phosphorylated extracellular-signal related kinase 1/2) as well as an imbalance between proapototic protein Bax and anti-apoptotic protein Bcl-2 expression. With administration of the flavonoid quercetin (50 mg/Kg i.p.) for four consecutive days following TAA, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were close to normal values in rats. Histological findings suggested that quercetin had a preventive effect on TAA-induced hepatic necrosis. Quercetin treatment caused significant decreases in lipid peroxide levels in the TAA-treated rats, with some changes in antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Quercetin also inhibited the change of the p-ERK1/2 by TAA and significantly prevented the increase in Bax/Bcl-2 ratio, thus preventing apoptosis. Findings indicate that quercetin may have a preventive effect on TAA-induced hepatotoxicity by modulating the oxidative stress parameters and apoptosis pathway. [ABSTRACT FROM PUBLISHER]

This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 μmol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (α-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1α, α-SMA, tumor necrosis factor-α, tumor growth factor-β, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 μmol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: The effects of polyoxyethylenglycerol triricinoleate 35 (Cremophor EL, CrEL) on markers of oxidative stress, nuclear factor kappa B (NF-κB) activation and inducible nitric oxide synthase (iNOS) expression were studied in the liver of male Wistar rats. Animals were randomly divided into three groups. Group Cr1 received, i.p., CrEL at 0.046ml/kg daily for 7 days, group Cr2 received CrEL at 0.33ml/kg and the controls were injected with CrEL vehicle (saline solution with 25% ethanol). Both alanine transaminase (ALT) and aspartate transaminase (AST) serum activities were significantly increased in the Cr2 group (+16% and +25%, respectively). AST activity was also higher in the Cr1 group when compared to control animals (+20%). The cytosolic concentration of thiobarbituric acid reactive substances (TBARS) increased in both groups of rats receiving CrEL (Cr1: +24%; Cr2: +33%). Reduced glutathione (GSH) concentration was not significantly modified at any of the CrEL doses, but both the hepatic concentration of oxidised glutathione (GSSG) (Cr1: +37%; Cr2: +84%) and the GSH/GSSG ratio (Cr1: −21%; Cr2: −45%) were significantly modified. CrEL induced no significant NF-κB activation, changes in p50 and p65 NF-κB subunits or induction of iNOS protein. Data obtained indicate that although high doses of CrEL cause oxidative stress, this is not enough to induce changes in NF-κB activation or iNOS expression. [Copyright &y& Elsevier]

Summary 1. The effects of the administration piperacillin on bile flow and biliary lipid secretion were studied in male Wistar rats. 2. Intravenous injection of piperacillin at doses ranging from 0.3 to 3.0 mmol/kg bodyweight led to an increase in its biliary concentration and excretion rate. Maximal biliary excretion was reached at a dose of 2.0 mmol/kg piperacillin. 3. Excretion of the antibiotic into bile was associated with a marked choleresis. A linear relationship was observed between bile flow and piperacillin excretion, 5.7 µL bile being produced per µmol piperacillin excreted into the bile. 4. Continuous i.v. infusion of piperacillin at 2.0 mmol/100 g per min did not result in significant changes in bile acid or cholesterol secretion, but biliary phospholipid secretion was markedly reduced. The inhibitory effect on phospholipid secretion was also present when biliary lipid output had been previously increased by an infusion of taurocholate (200 nmol/100 g per min). Addition of taurocholate did not reverse the impairment of phospholipid secretion induced by piperacillin. 5. These results indicate that acute administration of piperacillin in the rat induces a marked choleresis by stimulating bile acid-independent bile flow. The significant impairment in phospholipid secretion suggests a specific effect on intracellular supply and/or translocation across the canalicular membrane. [ABSTRACT FROM AUTHOR]