Publications by authors named "Maria Teresa Vallejo-Cremades"

18 Publications

  • Page 1 of 1

Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study.

Clin Transplant 2021 04 5;35(4):e14226. Epub 2021 Feb 5.

TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain.

Background: Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT).

Material/methods: Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups.

Results: Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups.

Conclusion: Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.
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http://dx.doi.org/10.1111/ctr.14226DOI Listing
April 2021

BML-111 treatment prevents cardiac apoptosis and oxidative stress in a mouse model of autoimmune myocarditis.

FASEB J 2020 08 16;34(8):10531-10546. Epub 2020 Jun 16.

Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.

Myocarditis is an inflammation of the myocardium that can progress to a more severe phenotype of dilated cardiomyopathy (DCM). Three main harmful factors determine this progression: inflammation, cell death, and oxidative stress. Lipoxins and their derivatives are endogenous proresolving mediators that induce the resolution of the inflammatory process. This study aims to determine whether these mediators play a protective role in a murine model of experimental autoimmune myocarditis (EAM) by treating with the lipoxin A analog BML-111. We observed that EAM mice presented extensive infiltration areas that correlated with higher levels of inflammatory and cardiac damage markers. Both parameters were significantly reduced in BML-treated EAM mice. Consistently, cardiac dysfunction, hypertrophy, and emerging fibrosis detected in EAM mice was prevented by BML-111 treatment. At the molecular level, we demonstrated that treatment with BML-111 hampered apoptosis and oxidative stress induction by EAM. Moreover, both in vivo and in vitro studies revealed that these beneficial effects were mediated by activation of Nrf2 pathway through CaMKK2-AMPKα kinase pathway. Altogether, our data indicate that treatment with the lipoxin derivative BML-111 effectively alleviates EAM outcome and prevents cardiac dysfunction, thus, underscoring the therapeutic potential of lipoxins and their derivatives to treat myocarditis and other inflammatory cardiovascular diseases.
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http://dx.doi.org/10.1096/fj.202000611RDOI Listing
August 2020

Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia-Reperfusion Injury in Mice.

Hepatology 2019 08 17;70(2):650-665. Epub 2019 Feb 17.

Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.

Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E (PGE ) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.
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http://dx.doi.org/10.1002/hep.30241DOI Listing
August 2019

NOD1 activation in cardiac fibroblasts induces myocardial fibrosis in a murine model of type 2 diabetes.

Biochem J 2017 02 1;474(3):399-410. Epub 2016 Nov 1.

Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.

Cardiac fibrosis and chronic inflammation are common complications in type 2 diabetes mellitus (T2D). Since nucleotide oligomerization-binding domain 1 (NOD1), an innate immune receptor, is involved in the pathogenesis of insulin resistance and diabetes outcomes, we sought to investigate its involvement in cardiac fibrosis. Here, we show that selective staining of cardiac fibroblasts from T2D (db/db;db) mice exhibits up-regulation and activation of the NOD1 pathway, resulting in enhanced NF-κB and TGF-β signalling. Activation of the TGF-β pathway in cardiac fibroblasts from db mice was prevented after inhibition of NF-κB with BAY-11-7082 (BAY). Moreover, fibrosis progression in db mice was also prevented by BAY treatment. Enhanced TGF-β signalling and cardiac fibrosis of db mice was dependent, at least in part, on the sequential activation of NOD1 and NF-κB since treatment of db mice with a selective NOD1 agonist induced activation of the TGF-β pathway, but co-administration of a NOD1 agonist plus BAY, or a NOD1 inhibitor prevented the NOD1-induced fibrosis. Therefore, NOD1 is involved in cardiac fibrosis associated with diabetes, and establishes a new mechanism for the development of heart fibrosis linked to T2D.
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http://dx.doi.org/10.1042/BCJ20160556DOI Listing
February 2017

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model.

PLoS One 2016 21;11(4):e0154159. Epub 2016 Apr 21.

Fundacion LAIR, Madrid, Spain.

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839760PMC
April 2017

Actin polymerisation after FCγR stimulation of human fibroblasts is BCL10 independent.

Clin Immunol 2016 Feb 14;163:120-2. Epub 2016 Jan 14.

Laboratory of Immunogenetics of Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain; Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain. Electronic address:

B-cell lymphoma 10 (BCL10) is not essential for actin polymerisation after FcγR stimulation in human fibroblasts.
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http://dx.doi.org/10.1016/j.clim.2016.01.003DOI Listing
February 2016

Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: proof of concept in rats.

J Transl Med 2015 Feb 1;13:46. Epub 2015 Feb 1.

Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ (Health Research Institute), Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain.

Background: Rat adipose tissue-derived-mesenchymal stem cells (rAD-MSCs) have proven to be safe in experimental animal models of stroke. However, in order to use human AD-MSCs (hAD-MSCs) as a treatment for stroke patients, a proof of concept is needed. We analyzed whether the xenogeneic hAD-MSCs were as safe and effective as allogeneic rAD-MSCs in permanent Middle Cerebral Artery Occlusion (pMCAO) in rats.

Methods: Sprague-Dawley rats were randomly divided into three groups, which were intravenously injected with xenogeneic hAD-MSCs (2 × 10(6)), allogeneic rAD-MSCs (2 × 10(6)) or saline (control) at 30 min after pMCAO. Behavior, cell implantation, lesion size and cell death were evaluated. Brain markers such as GFAP (glial fibrillary acid protein), VEGF (vascular endothelial growth factor) and SYP (synaptophysin) and tumor formation were analyzed.

Results: Compared to controls, recovery was significantly better at 24 h and continued to be so at 14 d after IV administration of either hAD-MSCs or rAD-MSCs. No reduction in lesion size or migration/implantation of cells in the damaged brain were observed in the treatment groups. Nevertheless, cell death was significantly reduced with respect to the control group in both treatment groups. VEGF and SYP levels were significantly higher, while those of GFAP were lower in the treated groups. At three months, there was no tumor formation.

Conclusions: hAD-MSCs and rAD-MSCs were safe and without side effects or tumor formation. Both treatment groups showed equal efficacy in terms of functional recovery and decreased ischemic brain damage (cell death and glial scarring) and resulted in higher angiogenesis and synaptogenesis marker levels.
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http://dx.doi.org/10.1186/s12967-015-0406-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322805PMC
February 2015

Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.

Stroke 2015 Jan 13;46(1):221-8. Epub 2014 Nov 13.

From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).

Background And Purpose: Translational research is beginning to reveal the importance of trophic factors as a therapy for cellular brain repair. The purpose of this study was to analyze whether brain-derived neurotrophic factor (BDNF) administration could mediate oligodendrogenesis and remyelination after white matter injury in subcortical stroke.

Methods: Ischemia was induced in rats by injection of endothelin-1. At 24 hours, 0.4 μg/kg of BDNF or saline was intravenously administered to the treatment and control groups, respectively. Functional evaluation, MRI, and fiber tract integrity on tractography images were analyzed. Proliferation (KI-67) and white matter repair markers (A2B5, 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase], adenomatous polyposis coli [APC], platelet-derived growth factor receptor alpha [PDGFR-α], oligodendrocyte marker O4 [O4], oligodendrocyte transcription factor [Olig-2], and myelin basic protein [MBP]) were analyzed at 7 and 28 days.

Results: The BDNF-treated animals showed less functional deficit at 28 days after treatment than the controls (P<0.05). Although T2-MRI did not show differences in lesion size at 7 and 28 days between groups, diffusion tensor imaging tractography analysis revealed significantly better tract connectivity at 28 days in the BDNF group than in the controls (P<0.05). Increased proliferation of oligodendrocyte progenitors was observed in treated animals at 7 days (P<0.05). Finally, the levels of white matter repair markers (A2B5, CNPase, and O4 at 7 days; Olig-2 and MBP at 28 days) were higher in the BDNF group than in the controls (P<0.05).

Conclusions: BDNF administration exerted better functional outcome, oligodendrogenesis, remyelination, and fiber connectivity than controls in rats subjected to subcortical damage in ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.114.006692DOI Listing
January 2015

NOD1 receptor is up-regulated in diabetic human and murine myocardium.

Clin Sci (Lond) 2014 Dec;127(12):665-77

†Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.

Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor NOD1 (nucleotide-binding and oligomerization domain 1) and the pathogenesis of diabetes, in monocytes and hepatic and adipose tissues. The aim of the present study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We have measured NOD1 protein in cardiac tissue from Type 2 diabetic (db) mice. Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an up-regulation of nuclear factor κB (NF-κB) and increased apoptosis. Heart tissue also exhibited an enhanced expression of pro-inflammatory cytokines. Selective NOD1 activation with C12-γ-D-glutamyl-m-diaminopimelic acid (iEDAP) resulted in an increased NF-κB activation and apoptosis, demonstrating the involvement of NOD1 both in wild-type and db mice. Moreover, HL-1 cardiomyocytes exposed to elevated concentrations of glucose plus palmitate displayed an enhanced NF-κB activity and apoptotic profile, which was prevented by silencing of NOD1 expression. To address this issue in human pathology, NOD1 expression was evaluated in myocardium obtained from patients with Type 2 diabetes (T2DMH) and from normoglycaemic individuals without cardiovascular histories (NH). We have found that NOD1 was expressed in both NH and T2DMH; however, NOD1 expression was significantly pronounced in T2DMH. Furthermore, both the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) and the apoptosis mediator caspase-3 were up-regulated in T2DMH samples. Taken together, our results define an active role for NOD1 in the heightened inflammatory environment associated with both experimental and human diabetic cardiac disease.
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http://dx.doi.org/10.1042/CS20140180DOI Listing
December 2014

Biofilm vs. planktonic bacterial mode of growth: which do human macrophages prefer?

Biochem Biophys Res Commun 2013 Nov 14;441(4):947-52. Epub 2013 Nov 14.

Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Spain.

Although the natural mode of bacterial growth in nature is as biofilm, almost all antimicrobial and immunological tests are routinely developed using planktonic inoculums. Bacterial biofilms protect the microbial community from external damage and promote the persistence of chronic infections. In this study, interactions between human macrophages and bacterial inoculums of planktonic and biofilm modes of growth have been explored using Escherichia coli (E. coli) K12. Human macrophages phagocytize planktonic E. coli more efficiently than bacteria grown in a biofilm. Moreover, they prefer to phagocytize planktonic bacteria. In this context, CD64 expression is involved. Our data indicate that bacteria with "a biofilm background" avoid phagocytosis by naïve macrophages, which could create a favorable environment for chronic infection. Our findings were corroborated in a clinical O25b-ST131 ESBL-producer E. coli isolate, which caused urinary tract infections.
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http://dx.doi.org/10.1016/j.bbrc.2013.11.012DOI Listing
November 2013

Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke.

J Cell Mol Med 2012 Oct;16(10):2280-90

Department of Neurology and Stroke Centre, La Paz University Hospital, Neuroscience Area of IdiPAZ (Health Research Institute), Autónoma University of Madrid, Madrid, Spain.

Brain repair involves a compendium of natural mechanisms that are activated following stroke. From a therapeutic viewpoint, reparative therapies that encourage cerebral plasticity are needed. In the last years, it has been demonstrated that modulatory treatments for brain repair such as trophic factor- and stem cell-based therapies can promote neurogenesis, gliogenesis, oligodendrogenesis, synaptogenesis and angiogenesis, all of which having a beneficial impact on infarct volume, cell death and, finally, and most importantly, on the functional recovery. However, even when promising results have been obtained in a wide range of experimental animal models and conditions these preliminary results have not yet demonstrated their clinical efficacy. Here, we focus on brain repair modulatory treatments for ischaemic stroke, that use trophic factors, drugs with trophic effects and stem cell therapy. Important and still unanswered questions for translational research ranging from experimental animal models to recent and ongoing clinical trials are reviewed here.
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http://dx.doi.org/10.1111/j.1582-4934.2012.01575.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823421PMC
October 2012

CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke.

Neurochem Int 2012 Feb 30;60(3):310-7. Epub 2011 Dec 30.

Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neurosciences Area of IdiPAZ, Health Research Institute, Autónoma University of Madrid, Madrid, Spain.

We investigated the effect of CDP-choline on brain plasticity markers expression in the acute phase of cerebral infarct in an experimental animal model. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO) and treated or not with CDP-choline (500 mg/kg) daily for 14 days starting 30 min after pMCAO. Functional status was evaluated with Roger's test; lesion volume with magnetic resonance imaging (MRI) and hematoxylin and eosin staining (H&E); cell death with TUNEL; cellular proliferation with BrdU immunohistochemistry; vascular endothelial growth factor (VEGF), synaptophysin, glial fibrillary acidic protein (GFAP) and low-density lipoprotein receptor-related protein (LRP) by immunofluorescence and Western-blot techniques. CDP-choline significantly improved functional recovery and decreased lesion volume on MRI, TUNEL-positive cell number and LRP levels at 14 days. In addition, CDP-choline significantly increased BrdU, VEGF and synaptophysin values and decreased GFAP levels in the peri-infarct zone compared with the infarct group. In conclusion, our data indicate that CDP-choline improved functional recovery after permanent middle cerebral artery occlusion in association with reductions in lesion volume, cell death and LRP expression. In fact, CDP-choline increased cell proliferation, vasculogenesis and synaptophysin levels and reduced GFAP levels in the peri-infarct area of the ischemic stroke.
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http://dx.doi.org/10.1016/j.neuint.2011.12.015DOI Listing
February 2012

Abnormal development of the enteric nervous system in rat embryos and fetuses with congenital diaphragmatic hernia.

Pediatr Surg Int 2011 Feb;27(2):165-73

Department of Pediatric Surgery, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046, Madrid, Spain.

Background/aim: Esophageal dilatation, gastroesophageal reflux, and intestinal obstruction have been demonstrated in CDH survivors. Abnormal esophageal and intestinal innervations were recently found in rats and babies with this disease. Our aim was to further characterize these malformations in embryos and fetal rats exposed to nitrofen.

Methods: Pregnant rats received either 100 mg nitrofen or vehicle on E9.5. Fetuses were recovered at E15, E18, and E21. Sections of esophagus and small bowel were histochemically stained with acetylcholinesterase (AChE) and immunostained for PGP9.5. PGP9.5 gen protein were measured on E21 and PGP9.5 mRNA on E15, E18 and E21. Comparisons between groups were made with non-parametrics tests.

Results: Histochemistry and immunohistochemistry showed deficient innervation in all anatomical areas studied at E15, E18, and E21, and WB confirmed this decrease in E21 fetuses. PGP9.5 messenger was decreased in nitrofen-exposed animals on E18 (esophagus) or E15 (small bowel), and increased on E21 in the esophagus and E18 in small bowel.

Conclusions: Development of the enteric nervous system of the esophagus, stomach, and small bowel is deficient in rat embryos and fetuses exposed to nitrofen. These anomalies could account in part for the long-term gastrointestinal morbidity observed in CDH survivors.
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http://dx.doi.org/10.1007/s00383-010-2788-xDOI Listing
February 2011

Exogenous ghrelin regulates proliferation and apoptosis in the hypotrophic gut mucosa of the rat.

Exp Biol Med (Maywood) 2010 Apr;235(4):463-9

Department of Experimental Surgery, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain.

Ghrelin is the natural endogenous ligand for growth hormone secretagogue receptors. This peptide regulates energy homeostasis and expenditure and is a potential link between gut absorptive function and growth. We hypothesized that ghrelin may induce a proliferative and antiapoptotic action promoting the recovery of the hypotrophic gut mucosa. Therefore, the aim of the study was to determine the action of exogenous ghrelin following gut mucosal hypotrophia in rats fed an elemental diet. An elemental diet provides readily absorbable simple nutrients and is usually given to patients with absorptive dysfunction. Male Wistar rats (n = 48) were fed the elemental diet for one week to induce mucosal hypotrophy and then treated for another week with systemic ghrelin and pair-fed with either a normoproteic or hyperproteic isocaloric liquid diet. Another group received a standard diet instead of the elemental diet and served as control (normotrophy). The elemental diet induced intestinal hypotrophia characterized by decreased proliferation in the ileum and increased apoptosis in jejunum and ileum. Ghrelin administration restored normal levels of proliferation in the ileum and apoptosis in the jejunum, with partial apoptosis restoration in the ileum. Ghrelin levels in plasma and fundus were increased in all groups, although the highest levels were found in rats treated with exogenous ghrelin. Ghrelin administration has a positive effect in the hypotrophic gut, regulating both proliferation and apoptosis towards a physiological balance counteracting the negative changes induced by an elemental diet in the intestines.
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http://dx.doi.org/10.1258/ebm.2009.009247DOI Listing
April 2010

Metalloproteinases shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes.

J Immunol 2007 Sep;179(6):4065-73

Research Unit, La Paz Hospital, Madrid, Spain.

Triggering receptors expressed on myeloid cell (TREM) proteins are a family of cell surface receptors that participate in diverse cellular processes such as inflammation, coagulation, and bone homeostasis. TREM-1, in particular, is expressed on neutrophils and monocytes and is a potent amplifier of inflammatory responses. LPS and other microbial products induce up-regulation of cell surface-localized TREM-1 and the release of its soluble form, sTREM-1. Two hypotheses have been advanced to explain the origin of sTREM-1: alternative splicing of TREM-1 mRNA and proteolytic cleavage(s) of mature, membrane-anchored TREM-1. In this report, we present conclusive evidence in favor of the proteolytic mechanism of sTREM-1 generation. No alternative splicing forms of TREM-1 were detected in monocytes/macrophages. Besides, metalloproteinase inhibitors increased the stability of TREM-1 at the cell surface while significantly reducing sTREM-1 release in cultures of LPS-challenged human monocytes and neutrophils. We conclude that metalloproteinases are responsible for shedding of the TREM-1 ectodomain through proteolytic cleavage of its long juxtamembrane linker.
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http://dx.doi.org/10.4049/jimmunol.179.6.4065DOI Listing
September 2007

6-Methylprednisolone down-regulates IRAK-M in human and murine osteoclasts and boosts bone-resorbing activity: a putative mechanism for corticoid-induced osteoporosis.

J Leukoc Biol 2007 Sep 18;82(3):700-9. Epub 2007 Jun 18.

Research Unit, La Paz Hospital, Madrid 28046, Spain.

Osteoclasts are large, multinucleated cells, which originate from the fusion of macrophages. They play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. IL-1R-associated kinase (IRAK)-M is a pseudokinase, which acts as a negative modulator of innate immune responses mediated by TLRs and IL-1R. Recently, it has been reported that IRAK-M also participates in the control of macrophage differentiation into osteoclasts. In addition, it was shown that IRAK-M knockout mice develop a strong osteoporosis phenotype, suggesting that down-regulation of this molecule activates osteoclast-mediated bone resorption. We studied the effect of the osteoporosis-inducing glucocorticoid, 6-methylprednisolone (6-MP), on IRAK-M expression in osteoclasts. Our results showed that osteoclasts, derived from THP-1 and RAW cells as well as human blood monocytes, differentiated into osteoclasts, express high levels of IRAK-M at mRNA and protein levels. In addition, 6-MP down-regulates IRAK-M expression, which correlates with an increased activation of bone resorption. These findings suggest a mechanism of corticosteroid-induced osteoporosis and open new avenues for treating this endemic disease of Western societies.
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http://dx.doi.org/10.1189/jlb.1106673DOI Listing
September 2007

A high-protein dietary treatment to intestinally hypotrophic rats induces ghrelin mRNA content and serum peptide level changes.

Clin Nutr 2005 Dec 14;24(6):904-12. Epub 2005 Jul 14.

Research Unit, Hospital Universitario La Paz, Madrid, Spain.

Background & Aims: Ghrelin is a peptide mainly secreted in stomach with a potent growth hormone releasing activity both in vitro and in vivo. The trophic mucosal effect of an enriched protein diet may be related with ghrelin and growth hormone plasma levels since peptides from the somatotrophic axis are well-known trophic factors. The possible relationship between nutritionally regulated active ghrelin plasma levels and the intestinal trophic effects of a high-protein diet was probed in rats with intestinal hypotrophy induced by an elemental diet.

Methods: Normal and elemental-diet-induced intestinally hypotrophic rats were treated with either a normoproteic or a high-protein diet for 1 week. It was determined ghrelin and IGF-1 plasma levels, fundic and duodenal ghrelin concentrations, ghrelin mRNA content and intestinal morphometric, proliferative and apoptotic parameters were determined. Growth hormone plasma levels were measured indirectly through IGF-1 plasma levels.

Results: Ghrelin plasma levels increased in elemental diet-induced intestinally hypotrophic rats fed either diet. Duodenum mRNA content, but not fundus, increased under the same conditions where plasma was studied. Dietary treatment did not modify the IGF-1 plasma levels. However, animals previously fed an elemental diet to induce intestinal hypotrophy had significantly lower levels of IGF-1.

Conclusions: The trophic effects on the intestine of an enriched protein diet are associated with increased ghrelin serum peptide level and mRNA content, and this increase might be related to the IGF-1 plasma levels in elemental diet-induced intestinally hypotrophic rats.
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http://dx.doi.org/10.1016/j.clnu.2005.05.018DOI Listing
December 2005
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