Bustos, M. (Matilde)
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- Interplay among cardiotrophin-1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration(Wiley Blackwell, 2005) Beraza, N. (Naiara); Prieto, J. (Jesús); Bustos, M. (Matilde); Iñiguez, M. (María); Marques, J.M. (Juan Martín); Martinez-Anso, E. (Eduardo)Prostaglandins are hepatoprotective molecules generated in liver regeneration by the rapid induction of cyclooxygenase-2 (COX-2). Cardiotrophin-1 (CT-1) and vascular endothelial growth factor (VEGF) are other hepatoprotective mediators upregulated at 24 hours after partial hepatectomy. The interactions among these molecules during liver regeneration have not yet been defined. Here we show that rats subjected to partial hepatectomy treated with NS-398, a specific COX-2 inhibitor, exhibited cell cycle arrest, increased hepatocyte apoptosis, persistent extracellular signal-regulated kinase (ERK) 1/2 activation, and increased interleukin-6 production. These changes were associated with downregulation of CT-1 and COX-1 and altered pattern of VEGF expression. Administration of an adenovirus encoding CT-1 to NS-398-treated rats restituted normal levels of COX-1, prostaglandins, and VEGF in the liver after partial hepatectomy and restored normal liver regeneration. Furthermore, the stimulation of isolated rat hepatocytes with CT-1 increased COX-1, COX-2, and VEGF messenger RNAs and prostaglandin synthesis. Conversely, the addition of prostaglandin E1 to the culture increased CT-1 and VEGF production. In conclusion, COX-2 activation and production of prostaglandins soon after partial hepatectomy are essential requirements for hepatocyte proliferation and for the correct induction of both CT-1 and VEGF. CT-1 can restore liver regeneration after COX-2 inhibition by increasing VEGF, COX-1 expression, and prostaglandin synthesis.
- Decreased cardiotrophin-1 levels are associated with a lower risk of developing the metabolic syndrome in overweight/obese children after a weight loss program(Elsevier, 2013) Martinez, J.A. (José Alfredo); Moreno-Aliaga, M. J. (María Jesús); Azcona-San-Julian, M.C. (María Cristina); Garcia-Calzon, S. (Sonia); Rendo-Urteaga, T. (Tara); Bustos, M. (Matilde); Chueca, M. (María); Oyarzabal, M. (M.); Martinez-Anso, E. (Eduardo); Marti-del-Moral, A. (Amelia)Objective: Cardiotrophin-1 (CT-1) shares some similarities with other cytokines, and participates in the control of energy metabolism. Higher circulating levels are observed in obese humans, but little information is gathered in weight loss (WL) programs. Therefore, we aimed to investigate the association of serum CT-1 levels with metabolic variables and the risk of developing metabolic syndrome (MetS) after a WL program in overweight/obese children. Subjects and Methods: Forty-four overweight/obese children (mean age 11.5 yr; 50% males) undergoing a 10-week WL program were enrolled. Subjects were dichotomized at the median of Body Mass Index-Standard Deviation Score (BMI-SDS) change, as high and low responders after intervention. Results: CT-1 levels were significantly reduced (-48 fmol/mL, p=0.043) in the high responder group after the WL program. They had significantly lower body weight (-3.7 kg, p<0.001), body fat mass (-8%, p<0.001), BMI-SDS (-0.78, p<0.001) and waist circumference (-5.4 cm, p<0.001), and a significant improvement in lipid and glucose profiles (p<0.05). Interestingly, decreased CT-1 levels significantly predicted changes in total cholesterol (41%) and LDL-cholesterol (28%). Moreover, in our participants the lower the CT-1 levels, the higher the reduction in MetS risk components, after the 10- week intervention, (p-ANCOVA=0.040, p-trend=0.024). Conclusion: We showed, for the first time, a reduction in serum CT-1 levels after a WL program and this decrease in CT-1 was strongly associated with a reduction in cholesterol levels and in MetS risk factors in overweight/obese children. Our findings may suggest that CT-1 could be an indirect marker for the diagnosis of MetS in this population.
- Cardiotrophin-1 is a key regulator of glucose and lipid metabolism(Elsevier, 2011) Martinez, J.A. (José Alfredo); Gimenez, I. (I.); Moreno-Aliaga, M. J. (María Jesús); Perez-Echarri, N. (Nerea); Viollet, B. (Benoit); Larequi-García, E. (Eduardo); Prieto, J. (Jesús); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz); Bustos, M. (Matilde)Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity. Acute treatment with rCT-1 decreased blood glucose in an insulin-independent manner and increased insulin-stimulated AKT phosphorylation in muscle. These changes were associated with stimulation of fatty acid oxidation, an effect that was absent in AMPKα2(-/-) mice. Chronic rCT-1 treatment reduced food intake, enhanced energy expenditure, and induced white adipose tissue remodeling characterized by upregulation of genes implicated in the control of lipolysis, fatty acid oxidation, and mitochondrial biogenesis and genes typifying brown fat phenotype. Moreover, rCT-1 reduced body weight and corrected insulin resistance in ob/ob and in high-fat-fed obese mice. We conclude that CT-1 is a master regulator of fat and glucose metabolism with potential applications for treatment of obesity and insulin resistance.
- Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas(Nature Publishing Group, 1999) Mazzolini, G. (Guillermo); Duarte, M. (Marina); Qian, C. (Cheng); Sangro, B. (Bruno); Melero, I. (Ignacio); Prieto, J. (Jesús); Bustos, M. (Matilde); Ruiz, J. (Juan); Galofre, J.C. (Juan Carlos)Stimulation of the antitumor immune response by dendritic cells (DC) is critically dependent on their tightly regulated ability to produce interleukin-12 (IL-12). To enhance this effect artificially, bone marrow (BM)-derived DC were genetically engineered to produce high levels of functional IL-12 by ex vivo infection with a recombinant defective adenovirus (AdCMVIL-12). DC-expressing IL-12 injected into the malignant tissue eradicated 50-100% well established malignant nodules derived from the injection of two murine colon adenocarcinoma cell lines. Successful therapy was dependent on IL-12 transfection and was mediated only by syngeneic, but not allogeneic BM-derived DC, indicating that compatible antigen-presenting molecules were required. The antitumor effect was inhibited by in vivo depletion of CD8+ T cells and completely abrogated by simultaneous depletion with anti-CD4 and anti-CD8 mAbs. Mice which had undergone tumor regression remained immune to a rechallenge with tumor cells, showing the achievement of long-lasting systemic immunity that also was able to reject simultaneously induced concomitant untreated tumors. Tumor regression was associated with a detectable CTL response directed against tumor-specific antigens probably captured by DC artificially released inside tumor nodules. Our results open the possibility of similarly treating the corresponding human malignancies.
- Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis(Elsevier, 1999) Eguinoa, E. (Ezequiel); Avila, M.A. (Matías Antonio); Rodriguez, J.A. (José Antonio); Carretero, M.V. (M. Victoria); Ruiz Garcia-Trevijano, E. (Elena); Fernandez, E. (Estefanía); Torres, L. (Luis); Bustos, M. (Matilde); Mato, J.M. (José María)Elevated plasma levels of homocysteine have been shown to interfere with normal cell function in a variety of tissues and organs, such as the vascular wall and the liver. However, the molecular mechanisms behind homocysteine effects are not completely understood. In order to better characterize the cellular effects of homocysteine, we have searched for changes in gene expression induced by this amino acid. Our results show that homocysteine is able to induce the expression and synthesis of the tissue inhibitor of metalloproteinases-1 (TIMP-1) in a variety of cell types ranging from vascular smooth muscle cells to hepatocytes, HepG2 cells and hepatic stellate cells. In this latter cell type, homocysteine also stimulated alpha 1(I) procollagen mRNA expression. TIMP-1 induction by homocysteine appears to be mediated by its thiol group. Additionally, we demonstrate that homocysteine is able to promote activating protein-1 (AP-1) binding activity, which has been shown to be critical for TIMP-1 induction. Our findings suggest that homocysteine may alter extracellular matrix homeostasis on diverse tissular backgrounds besides the vascular wall. The liver could be considered as another target for such action of homocysteine. Consequently, the elevated plasma levels of this amino acid found in different pathological or nutritional circumstances may cooperate with other agents, such as ethanol, in the onset of liver fibrosis.
- A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury(Elsevier, 2003) Greenwel, P. (Patricia); Dotor, J. (Javier); Castilla-Cortazar, I. (Inma); Borras-Cuesta, F. (Francisco); Peñuelas-Sanchez, I. (Ivan); Lechuga, M.C.G. (María del Carmen G.); Rojkind, M. (Marcos); Rodriguez-Ortigosa, C.M. (Carlos M.); Blanco, G. (Gemma); Ezquerro, I.J. (Ignacio José); Prieto, J. (Jesús); Bustos, M. (Matilde); Lasarte, J.J. (Juan José)Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine, which displays potent profibrogenic effects and is highly expressed in fibrotic livers. For this reason, development of TGF-B1 inhibitors might be of great importance to control liver fibrogenesis as well as other undesired side effects due to this cytokine. Potential peptide inhibitors of TGF-beta1 (derived from TGF-beta1 and from its type III receptor) were tested in vitro and in vivo using different assays. Peptides P11 and P12, derived from TGF-beta1, and P54 and P144, derived from its type III receptor, prevented TGF-beta1-dependent inhibition of MV1Lu proliferation in vitro and markedly reduced binding of TGF-beta1 to its receptors. P144 blocked TGF-beta1-dependent stimulation of a reporter gene under the control of human alpha2(I) collagen promoter. Intraperitoneal administration of P144 also showed potent antifibrogenic activity in vivo in the liver of rats receiving CCl4. These rats also showed a significant decrease in the number of activated hepatic stellate cells as compared with those treated with saline only. These results suggest that short synthetic peptides derived from TGF-beta1 type III receptor may be of value in reducing liver fibrosis in chronic liver injury.
- Eicosapentaenoic acid stimulates AMP-activated protein kinase and increases visfatin secretion in cultured murine adipocytes(Portland Press, 2009) Martinez, J.A. (José Alfredo); Lorente-Cebrian, S. (Silvia); Moreno-Aliaga, M. J. (María Jesús); Bustos, M. (Matilde); Marti-del-Moral, A. (Amelia)Visfatin is an adipokine highly expressed in visceral AT (adipose tissue) of humans and rodents, the production of which seems to be dysregulated in excessive fat accumulation and conditions of insulin resistance. EPA (eicosapentaenoic acid), an n−3 PUFA (polyunsaturated fatty acid), has been demonstrated to exert beneficial effects in obesity and insulin resistance conditions, which have been further linked to its reported ability to modulate adipokine production by adipocytes. TNF-α (tumour necrosis factor-α) is a pro-inflammatory cytokine whose production is increased in obesity and is involved in the development of insulin resistance. Control of adipokine production by some insulin-sensitizing compounds has been associated with the stimulation of AMPK (AMP-activated protein kinase). The aim of the present study was to examine in vitro the effects of EPA on visfatin production and the potential involvement of AMPK both in the absence or presence of TNF-α. Treatment with the pro-inflammatory cytokine TNF-α (1 ng/ml) did not modify visfatin gene expression and protein secretion in primary cultured rat adipocytes. However, treatment of these primary adipocytes with EPA (200 μmol/l) for 24 h significantly increased visfatin secretion (P<0.001) and mRNA gene expression (P<0.05). Moreover, the stimulatory effect of EPA on visfatin secretion was prevented by treatment with the AMPK inhibitor Compound C, but not with the PI3K (phosphoinositide 3-kinase) inhibitor LY294002. Similar results were observed in 3T3-L1 adipocytes. Moreover, EPA strongly stimulated AMPK phosphorylation alone or in combination with TNF-α in 3T3-L1 adipocytes and pre-adipocytes. The results of the present study suggest that the stimulatory action of EPA on visfatin production involves AMPK activation in adipocytes.
- Obesidad, inflamación e insulino-resistencia: papel de los ligandos del receptor gp 130(Gobierno de Navarra. Departamento de Salud, 2008) Martinez, J.A. (José Alfredo); Moreno-Aliaga, M. J. (María Jesús); Prieto, J. (Jesús); Marcos, B. (Beatriz); Bustos, M. (Matilde)Obesity can be considered as a low grade inflammatory disease, characterized by increased plasma levels of proinflammatory cytokines such as tumoral necrosis factor-a (TNF-a), and acute phase reactant proteins like C-reactive protein. In this context, some cytokines of the interleukin-6 (IL-6) family have been involved in the inflammatory processes associated to obesity. In addition to IL-6, the IL-6 cytokine family includes IL-11, ciliary neurotrophic factor (cntf), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF) y Oncostatin M (OsM). These proteins are also known as gp130 cytokines because all of them exert their action via the glycoprotein 130 (gp130) as a common transducer protein within their functional receptor complexes. However, their role in obesity and related disorders is controversial; thus, whereas some studies have described the involvement of gp130 cytokines in the development of obesity and its related cluster of pathophysiologic conditions like insulin-resistance, fatty liver and cardiovascular diseases, other trials have proposed the gp130 receptor ligands as therapeutic targets in the treatment of obesity and its related disorders. In fact, CNTF treatment has demonstrated to be effective in the reduction of body weight, by promoting the inhibition of food intake and the activation of the energy expenditure, together with an improvement of insulin sensitivity. This review analyzes the potential therapeutic role of some of the gp130 ligands in obesity and related diseases.
- Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats(Wb saunders, 2003) Baixeras, E. (Elena); Beraza, N. (Naiara); Alzuguren, P. (Pilar); Prieto, J. (Jesús); Bustos, M. (Matilde); Bordet, T. (Thierry); Lasarte, J.J. (Juan José)BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
- Cardiotrophin-1 promotes a high survival rate in rabbits with lethal fulminant hepatitis of viral origin(American Society for Microbiology, 2011) Riezu-Boj, J.I. (José Ignacio); Alvarez, M. (Marcelino); Gonzalez-Gallego, J. (Javier); San-Miguel, B. (Beatriz); Gonzalez, I. (Iranzu); Larrea, E. (Esther); Prieto, J. (Jesús); Crespo, I. (Irene); Tuñon, M.J. (María Jesús); Bustos, M. (Matilde)Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twenty-four rabbits were infected with 2 × 10(4) hemagglutination units of RHDV. Twelve received five doses of CT-1 (100 μg/kg) starting at 12 h postinfection (hpi) (the first three doses every 6 h and then two additional doses at 48 and 72 hpi), while the rest received saline. The animals were analyzed for survival, serum biochemistry, and viral load. Another cohort (n = 22) was infected and treated similarly, but animals were sacrificed at 30 and 36 hpi to analyze liver histology, viral load, and the expression of factors implicated in liver damage and repair. All infected rabbits that received saline died by 60 hpi, while 67% of the CT-1-treated animals survived until the end of the study. Treated animals showed improved liver function and histology, while the viral loads were similar. In the livers of CT-1-treated rabbits we observed reduction of oxidative stress, diminished PARP1/2 and JNK activation, and decreased inflammatory reaction, as reflected by reduced expression of tumor necrosis factor alpha, interleukin-1β, Toll-like receptor 4, VCAM-1, and MMP-9. In addition, CT-1-treated rabbits exhibited marked upregulation of TIMP-1 and increased expression of cytoprotective and proregenerative growth factors, including platelet-derived growth factor B, epidermal growth factor, platelet-derived growth factor receptor β, and c-Met. In conclusion, in a lethal form of acute viral hepatitis, CT-1 increases animal survival by attenuating inflammation and activating cytoprotective mechanisms, thus representing a promising therapy for ALF of viral origin.