Elena Baixeras

Biomedical Research Institute of Malaga (IBIMA), Málaga, Andalusia, Spain

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Publications (47)223.33 Total impact

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    ABSTRACT: Background and purpose: Lipogenesis is intimately controlled by hormonal and cytokine regulation as well as by nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in liver. We have investigated the role of IL-6 in mediating fasting/re-feeding changes in the abundance of hepatic lipogenic enzymes. Experimental approach: Gene and protein expression for lipogenic enzymes were examined in livers of wild type (WT) and IL-6 deficient (IL-6(-/-) ) mice during fasting and re-feeding. The effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated through siRNA approach in human HepG2 cells. Key results: Under feeding, hepatic expression of lipogenic genes presented similar time kinetics of up-regulation in both WT and IL-6(-/-) mice. Under fasting, expression of lipogenic genes decreased gradually over time in both strains, though the initial drop was more marked in IL-6(-/-) mice. Protein amounts of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of fasting period. In WT, circulating IL-6 paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed direct association between IL-6-mediated signalling and up-regulation of hepatic lipogenic enzyme gene expression. Moreover, silencing STAT3 in HepG2 cells derogated IL-6 mediated up-regulation of lipogenic gene transcription levels. Conclusions and implications: IL-6 sustains levels of hepatic lipogenic enzymes during fasting suggesting a direct involvement of STAT3. Our findings warn about clinical use of the STAT3-associated signalling cytokines particularly against steatosis. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Cannabinoid CB1 receptors peripherally modulate energy metabolism. Here, we investigated the role of CB1 receptors in the expression of glucose/pyruvate/tricarboxylic acid (TCA) metabolism in rat abdominal muscle. Dihydrolipoamide dehydrogenase (DLD), a flavoprotein component (E3) of α-ketoacid dehydrogenase complexes with diaphorase activity in mitochondria, was specifically analyzed. After assessing the effectiveness of the CB1 receptor antagonist AM251 (3 mg kg-1, 14 days) on food intake and body weight, we could identified seven key enzymes from either glycolytic pathway or TCA cycle-regulated by both diet and CB1 receptor activity-through comprehensive proteomic approaches involving two-dimensional electrophoresis and MALDI-TOF/LC-ESI trap mass spectrometry. These enzymes were glucose 6-phosphate isomerase (GPI), triosephosphate isomerase (TPI), enolase (Eno3), lactate dehydrogenase (LDHa), glyoxalase-1 (Glo1) and the mitochondrial DLD, whose expressions were modified by AM251 in hypercaloric diet-induced obesity. Specifically, AM251 blocked high-carbohydrate diet (HCD)-induced expression of GPI, TPI, Eno3 and LDHa, suggesting a down-regulation of glucose/pyruvate/lactate pathways under glucose availability. AM251 reversed the HCD-inhibited expression of Glo1 and DLD in the muscle, and the DLD and CB1 receptor expression in the mitochondrial fraction. Interestingly, we identified the presence of CB1 receptors at the membrane of striate muscle mitochondria. DLD over-expression was confirmed in muscle of CB1-/- mice. AM251 increased the pyruvate dehydrogenase and glutathione reductase activity in C2C12 myotubes, and the diaphorase/oxidative activity in the mitochondria fraction. These results indicated an up-regulation of methylglyoxal and TCA cycle activity. Findings suggest that CB1 receptors in muscle modulate glucose/pyruvate/lactate pathways and mitochondrial oxidative activity by targeting DLD.
    Full-text · Article · Dec 2015 · PLoS ONE
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    ABSTRACT: Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg−1) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatmen
    Full-text · Article · Oct 2015 · Disease Models and Mechanisms
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    ABSTRACT: Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but the plasma/tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild type (WT) and IL-6-deficient (IL-6-/-) mice models. Additionally, HFD-fed IL-6-/- mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of Carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase (p-AMPK) phosphorylation and downregulation of hepatic lipogenic enzymes Fatty acid synthase (FAS) and Stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6-/- mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6-/- mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, the rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. Conclusion: in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis process.
    Full-text · Article · May 2015 · Disease Models and Mechanisms
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    ABSTRACT: Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism. © 2015 Society for the Study of Addiction.
    Full-text · Article · May 2015 · Addiction Biology
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    ABSTRACT: β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating the peroxisome proliferator-activating receptor-α (PPARα) in the white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association was monitored on feeding, thermogenesis, β-oxidation and lipid/cholesterol metabolism in epididymal (e)WAT. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as lowered plasma levels of triglycerides, cholesterol, NEFAs and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes, as the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were over-expressed in eWAT. The enhancement of the fatty acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied with an up-regulation of de novo lipogenesis and a reduction of the unsaturated fatty acid synthesis enzyme Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promote therapeutic adipocyte remodelling in eWAT that confer a potential clinical utility for the treatment of obesity.
    Full-text · Article · Oct 2013 · Disease Models and Mechanisms
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    ABSTRACT: BACKGROUND: LFABP plays a critical role in the uptake and intracellular transport of fatty acids (FA) and other peroxisome proliferator-activated receptor alpha (PPARα) ligands. PPARα activation by PPARα ligands bound to LFABP results in gene expression of FA oxidation enzymes and de novo LFABP. The cytokine IL-6 is involved in regulating liver lipid oxidation. AIMS: To study the ability of IL-6 to modulate the expression of the LFABP in hepatocytes. Methods: HepG2 and mouse primary hepatocytes were used to test LFABP mRNA and protein expression after IL-6 and PPARα-ligand treatments. Mice lacking IL-6 and wild-type C57Bl/6 were subjected to a fasting/re-feeding cycle to monitor hepatic LFABP mRNA kinetics after food intake. RESULTS: In hepatocyte cultures, IL-6 treatment stimulated a LFABP mRNA sustained expression. Combined treatment of IL-6 plus PPARα ligands further enhanced LFABP gene and protein expression. In contrast, pretreatment with the PPARα-antagonist GW-6471 prevented the up-regulation of LFABP mRNA induced by IL-6 in the late phase of LFABP kinetics. Furthermore, the up-regulation of LFABP mRNA observed in the liver of wild-type mice 8 h after re-feeding was absent in mice lacking IL-6. CONCLUSIONS: IL-6 induces LFABP kinetics in hepatocytes and is partially dependent on PPARα. The maximum increase in LFABP expression occurs when the stimulation with IL-6 and PPARα-ligands takes place simultaneously. The in vivo results indicate a postprandial regulation of LFABP that correlates with the presence of IL-6. These effects may have important implications in the postprandial increase in FA uptake and intracellular trafficking in the liver.
    Full-text · Article · Mar 2013 · Liver international: official journal of the International Association for the Study of the Liver
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    ABSTRACT: The current epidemic of obesity in western countries is being worsened by the lack of effective pharmacotherapies. The apparent success of a central nervous system-acting cannabinoid CB1 receptor antagonist-based treatment for obesity was hampered by the appearance of psychiatric side effects in certain patients. These adverse effects forced its withdrawal from the market. However, the discovery that the main beneficial metabolic effects of cannabinoid CB1 receptor antagonists were derived of its activity in peripheral tissues, including the adipose tissue, opened the possibility of rescuing this type of therapy. This goal might be achieved by differential medicinal chemistry approaches. The present review examines these options that include peripheral-restricted cannabinoid CB1 receptor antagonists, dual ligands and combinatorial therapies using sub-effective doses of CB1 receptor antagonists that might be devoid of side effects.
    Full-text · Article · Dec 2012
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    ABSTRACT: Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.
    Full-text · Article · Jan 2012 · AJP Endocrinology and Metabolism

  • No preview · Article · Jan 2010 · Diabetes
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    ABSTRACT: Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported.
    No preview · Article · Nov 2009 · Molecular Endocrinology
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    ABSTRACT: Glucokinase hyperinsulinism is a rare variant of congenital hyperinsulinism caused by activating mutations in the glucokinase gene and has been reported so far to be a result of overactivity of glucokinase within the pancreatic beta-cell. Here we report on a new patient with difficulties to diagnose persistent hyperinsulinism and discuss diagnostic procedures of this as well as the other reported individuals. After neonatal hypoglycemia, the patient was reevaluated at the age of 3 years for developmental delay. Morning glucose after overnight fast was 2.5-3.6 mmol/l. Fasting tests revealed supressed insulin secretion at the end of fasting (1.4-14.5 pmol/l). In addition, diagnostic data of the patients reported so far were reviewed. A novel heterozygous missense mutation in exon 10 c.1354G>C (p.Val452Leu) was found and functional studies confirmed the activating mutation. There was no single consistent diagnostic criterion found for our patient and glucokinase hyperinsulinism individuals in general. Often at the time of hypoglycemia low insulin levels were found. Therefore insulin concentrations at hypoglycemia, or during fasting test as well as reactive hypoglycemia after an oral glucose tolerance test were not conclusive for all patients. A glucose lowering effect in extra-pancreatic tissues independent from hyperinsulinism that results in diagnostic difficulties may contribute to underestimation of glucokinase hyperinsulinism. Mutational analysis of the GCK-gene should be performed in all individuals with unclear episodes of hypoglycemia even without documented hyperinsulinism during hypoglycemia. Delay of diagnosis might result in mental handicap of the affected individuals.
    No preview · Article · Apr 2009 · Hormone and Metabolic Research
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    ABSTRACT: We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes N-acyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoid-degrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase. Real-time PCR, western blotting and immunocytochemistry were used to analyse the presence of endocannabinoid-related proteins and genes. Static secretion experiments were used to examine the effects of activating CB1 or CB2 on insulin, glucagon and somatostatin secretion and to measure changes in 2-arachidonoylglycerol (2-AG) levels within islets. Analyses were performed in isolated human islets and in paraffin-embedded sections of human pancreas. Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose). Immunofluorescence revealed that CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells. CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells. In vitro experiments revealed that CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional. Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.
    Full-text · Article · Apr 2008 · Diabetologia
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    ABSTRACT: Se ha estudiado mediante inmunohistoquímica la presencia de los receptores cannabinoides CB1 y CB2 en el páncreas endocrino de rata, ratón y humanos. Esto ha puesto de relieve considerables diferencias inter-especie. Además, estudios in vivo en ratas e in vitro con islotes humanos muestran que los cannabinoides administrados exógenamente son capaces de modular la homeostasis de la glucosa modificando los niveles de insulina y glucagón. Finalmente, hemos detectado diferencias en los niveles intra-islote del endocannabinoide 2-AG. Todos estos resultados sugieren la presencia de un sistema endocannabinoide activo en el páncreas endocrino de mamíferos.
    Full-text · Chapter · Jan 2008
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    ABSTRACT: Combination therapy with interferon-alpha (IFNalpha) and ribavirin is the current treatment of choice for hepatitis C virus (HCV) infection. However, an important number of patients fail to respond to this therapeutic strategy. Factors determining IFN responsiveness are not well understood, and assessment of biomarkers that predict the response to IFN therapy in HCV patients is necessary. Several studies show that particular HCV proteins are able to block IFN function through interaction with important IFN-signal mediators, such as signal transducers and activators of transcription (STATs). We performed immunostaining analysis of STATs in liver tissue from IFN-responder vs. non-responder HCV patients in order to compare the expression profile of these proteins between both groups. Tissue arrays of liver biopsies were used to study the expression of STAT1, STAT2, STAT5 and PIAS1 (protein inhibitor of activated STAT1). Robust and higher expression levels of STAT1, STAT2 and STAT5 in liver tissue from HCV patients were found when compared with samples from healthy donors. However, no significant differences were observed between IFN-responder and -non-responder groups, but rather increasing levels of STAT1, STAT2 and STAT5 paralleled the degree of liver injury. Importantly, PIAS1 expression in the nucleus of most hepatocytes in HCV tissue biopsy sections, particularly of non-responder HCV patients, strongly indicated a regulatory effect on STAT1-DNA binding, likely affecting the IFN late signalling. In conclusion, our evidence indicates that intense PIAS1 nuclear staining, widely distributed in hepatocytes of infected livers, could be a good predictive factor of a defective response to IFN treatment, and a biomarker that is easily detectable by immunostaining during standard histopathological liver biopsy analysis.
    No preview · Article · Nov 2007 · The Journal of Pathology
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    ABSTRACT: The endogenous cannabinoid acylethanolamide AEA (arachidonoylethanolamide; also known as anandamide) participates in the neuroadaptations associated with chronic ethanol exposure. However, no studies have described the acute actions of ethanol on AEA production and degradation. In the present study, we investigated the time course of the effects of the intraperitoneal administration of ethanol (4 g/kg of body mass) on the endogenous levels of AEA in central and peripheral tissues. Acute ethanol administration decreased AEA in the cerebellum, the hippocampus and the nucleus accumbens of the ventral striatum, as well as in plasma and adipose tissue. Parallel decreases of a second acylethanolamide, PEA (palmitoylethanolamide), were observed in the brain. Effects were observed 45-90 min after ethanol administration. In vivo studies revealed that AEA decreases were associated with a remarkable inhibition of the release of both anandamide and glutamate in the nucleus accumbens. There were no changes in the expression and enzymatic activity of the main enzyme that degrades AEA, the fatty acid amidohydrolase. Acute ethanol administration did not change either the activity of N-acyltransferase, the enzyme that catalyses the synthesis of the AEA precursor, or the expression of NAPE-PLD (N-acylphosphatidylethanolamine-hydrolysing phospholipase D), the enzyme that releases AEA from membrane phospholipid precursors. These results suggest that receptor-mediated release of acylethanolamide is inhibited by the acute administration of ethanol, and that this effect is not derived from increased fatty acid ethanolamide degradation.
    Full-text · Article · Jun 2007 · Biochemical Journal
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    ABSTRACT: Interferon-alpha5 (IFN-alpha5) is the main IFN-alpha subtype expressed in the liver. Hepatitis C virus (HCV) infection is associated with low IFN-alpha5 mRNA levels, possibly reflecting an escape mechanism of the virus. In this work, we sought to compare IFN-alpha2 and IFN-alpha5 with respect to activation of early cell signaling cascades and induction of antiviral genes in the human hepatoma HepG2 and Huh7 cell lines. We found that the Tyr701 phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN-alpha5 than when using IFN-alpha2. Similarly, Tyr(1054/1055) phosphorylation kinetics of Tyk2 were more intense after exposure to IFN-alpha5 than when using IFN-alpha2. Concomitantly, Tyr705 phosphorylation of Stat3 was higher after stimulation with IFN-alpha5 than with IFN-alpha2. In parallel to these findings, the mRNA levels of the antiviral IFN-inducible gene 2',5'-oligoadenylate synthetase were higher in cell samples treated with IFN-alpha5 than with IFN-alpha2. These findings suggest that interaction of IFN-alpha5 and IFN-alpha2 subtypes with IFN type I receptor occurs differently, and this affects the intensity of expression of antiviral genes. In conclusion, our data show that in hepatocytic cells, IFN-alpha5 induces stronger signaling and higher expression of antiviral genes than IFN-alpha2. These data warrant clinical trials to evaluate the efficacy of IFN-alpha5 in chronic viral hepatitis.
    Full-text · Article · Sep 2004 · Journal of Interferon & Cytokine Research
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    ABSTRACT: Systemic treatment with an anti-ICAM-2 monoclonal antibody (mAb; EOL4G8) eradicates certain established mouse tumors through a mechanism dependent on the potentiation of a CTL-mediated response. However, well-established tumors derived from the MC38 colon carcinoma cell line were largely refractory to this treatment as well as to intratumor injection of a recombinant adenovirus encoding interleukin-12 (IL-12; AdCMVIL-12). We sought to design combined therapy strategies with AdCMVIL-12 plus anti-ICAM-2 mAbs and to identify their mechanism of action. Analysis of antitumor and toxic effects were performed with C57BL/6 mice bearing established MC38 tumors. Anti-ovalbumin T-cell receptor transgenic mice and tumors transfected with this antigen were used for in vitro and in vivo studies on activation-induced cell death (AICD) of CD8(+) T cells. Combined treatment with various systemic doses of EOL4G8 mAb plus intratumor injection of AdCMVIL-12 induced complete regression of MC38 tumors treated 7 days after implantation. Unfortunately, most of such mice succumbed to a systemic inflammatory syndrome that could be prevented if IFN-gamma activity were neutralized once tumors had been rejected. Importantly, dose reduction of EOL4G8 mAb opened a therapeutic window (complete cure of 9 of 18 cases without toxicity). We also show that ICAM-2 ligation by EOL4G8 mAb on activated CTLs prevents AICD, thus extending IFN-gamma production. Combination of intratumor gene transfer of IL-12and systemic anti-ICAM-2 mAb display synergistic therapeutic and toxic effects. CTL life extension resulting from AICD inhibition by anti-ICAM-2 mAbs is the plausible mechanism of action.
    Preview · Article · Oct 2003 · Clinical Cancer Research
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    ABSTRACT: Cardiotrophin-1 (CT-1) is a member of the interleukin 6 (IL-6) family of cytokines, which protect cardiac myocytes against thermal and ischemic insults. In this study, we investigated the expression of CT-1 by liver cells and its possible hepatoprotective properties. We analyzed the production, signaling, and antiapoptotic properties of CT-1 in hepatocytes and the expression of this cytokine during liver regeneration. We also investigated whether CT-1 might exert protective effects in animal models of liver damage. We found that CT-1 is up-regulated during liver regeneration and exerts potent antiapoptotic effects on hepatocytic cells. Hepatocytes cultured under serum starvation or stimulated with the pro-apoptotic cytokine transforming growth factor beta (TGF-beta) produce CT-1, which behaves as an autocrine/paracrine survival factor. Treatment with an adenovirus encoding CT-1 efficiently protects rats against fulminant liver failure after subtotal hepatectomy, an intervention that causes 91% mortality in control animals whereas 54% of those receiving CT-1 gene therapy were long-term survivors. This protective effect was associated with reduced caspase-3 activity and activation of the antiapoptotic signaling cascades signal transducer and activator of transcription (Stat-3), extracellular regulated kinases (Erk) 1/2, and Akt in the remnant liver. Gene transfer of CT-1 to the liver also abrogated Concanavalin A (Con-A) liver injury and activated antiapoptotic pathways in the hepatic tissue. Similar protection was obtained by treating the animals with 5 microg of recombinant CT-1 given intravenously before Con-A administration. We show that CT-1 is a hepatocyte survival factor that efficiently reduces hepatocellular damage in animal models of acute liver injury. Our data point to CT-1 as a new promising hepatoprotective therapy.
    Full-text · Article · Aug 2003 · Gastroenterology
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    ABSTRACT: Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4+ T cells responding to HCV core in patients with chronic HCV infection. However, CD4+ response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4+ response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.
    Full-text · Article · Jun 2002 · Journal of Virology

Publication Stats

1k Citations
223.33 Total Impact Points

Institutions

  • 2016
    • Biomedical Research Institute of Malaga (IBIMA)
      Málaga, Andalusia, Spain
  • 2015
    • University of Malaga
      Málaga, Andalusia, Spain
  • 2007-2013
    • Hospital Regional Universitario de Málaga
      Málaga, Andalusia, Spain
    • University of California, Irvine
      • Department of Pharmacology
      Irvine, California, United States
  • 2009
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2003
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2001-2003
    • Universidad de Navarra
      • • School of Medicine
      • • Department of Internal Medicine
      Iruña, Navarre, Spain
  • 2000
    • Boston University
      • Department of Biochemistry
      Boston, Massachusetts, United States
  • 1999-2000
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1994-1997
    • Universidad Autónoma de Madrid
      • • Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM)
      • • Department of Immunology
      Madrid, Madrid, Spain
  • 1996
    • Spanish National Centre for Biotechnology
      Madrid, Madrid, Spain
  • 1995
    • Complutense University of Madrid
      Madrid, Madrid, Spain
  • 1990
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 1987
    • Centro de Investigaciones Biológicas
      Madrid, Madrid, Spain