Heme oxygenase-1 is required for angiogenic function of bone marrow-derived progenitor cells : role in therapeutic revascularization

Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs

Density functional theory based screening of ternary alkali-transition metal borohydrides: A computational material design project

The dissociation of molecules, even the most simple hydrogen molecule, cannot be described accurately within density functional theory because none of the currently available functionals accounts for strong on-site correlation. This problem led to a discussion of properties that the local Kohn-Sham potential has to satisfy in order to correctly describe strongly correlated systems. We derive an analytic expression for the nontrivial form of the Kohn-Sham potential in between the two fragments for the dissociation of a single bond. We show that the numerical calculations for a one-dimensional two-electron model system indeed approach and reach this limit. It is shown that the functional form of the potential is universal, i.e., independent of the details of the two fragments.We acknowledge funding by the Spanish MEC (Grant No. FIS2007-65702-C02-01), “Grupos Consolidados UPV/EHU del Gobierno Vasco” (Grant No. IT-319-07), and the European Community through e-I3 ETSF project (Grant Agreement No. 211956).Peer reviewe

Esential cases on natural causation

Bibliografija išnašose ; Rodyklė: p. 619-627This volume of the „Digest of European Tort Law" is the first product of a most ambitious research project: a collection of court decisions from almost all European jurisdictions on the most fundamental aspects of tort law. These cases are not only accumulated, but also structured, analysed and commented both from a national as well as a comparative perspective. Historical aspects are also considered, as are future trends, as outlined by current projects on the harmonisation of European tort laws. This complex comparative study shall thereby not only offer guidance for researching cross-border cases, but also allow a discussion of such harmonisation projects on the basis of real-life case settings. This first volume covers one key aspect of tortious liability – natural causation. The conditio sine qua non rule is examined and tested throughout all jurisdictions, in particular with an eye on whether and to what extent courts are willing to deviate from the strict concept of this formulaMykolo Romerio universiteta

Essential cases on damage

Bibliogr. išnašoseThe increasing Europeanisation of the law of delict/torts has produced textbooks, casebooks, monographs, and also sets of model rules of a genuinely European character. A major gap still existing today relates to the experiences gathered in the national legal systems over the past decades. The present work attempts to fill this gap for one key element of tort law: the notion of damage. It thus does what the previous volume in the ‘Digest of European Tort Law’ series did for another key element, ie natural causation. Once again, the publication contains a selection of the most important cases decided in 26 states across Europe as well as by the European Court of Justice. For each case the facts and the relevant court decision are presented, and the decision is analysed within the wider context of the development of the respective legal system. In addition, the editors provide comparative analyses of the case law reported in this volume concerning all the specific problems raised under the heading of damage. The publication also looks into how key cases would be resolved under the European model rules drafted in the field of tort law; and it also highlights cases from earlier periods of legal history. The editors believe that the material gathered here may provide guidance for an organic convergence of the national legal systems in Europe. It constitutes the basis of an acquis commun that is infinitely richer (though also much more complex) than the rather bland and abstract concepts contained in national codifications, European legislation, and the modern model rulesMykolo Romerio universitetasPrivatinės teisės katedraVytauto Didžiojo universiteta

Essential cases on misconduct

Bibliografija išnašoseThe various national European legal systems offer a broad range of responses to the question of what can be regarded as wrongful behaviour or fault. The present work systematically examines these two important prerequisites for tortious liability under the combined heading of ‘misconduct’. Unlike current textbooks, national casebooks and monographs, it builds on the experiences gathered in the national legal systems over the past decades and thereby fills a major gap which still exists today. It thus does what the previous volumes in the ‘Digest of European Tort Law’ series did for other key elements of tort law, namely natural causation and damage. Once again, the publication contains a selection of the most important cases from 28 states across Europe as well as cases handed down by European Union courts; it also highlights cases from earlier periods of legal history. For each case, the facts and the relevant court decision are presented and these are then accompanied by an analytical commentary. In addition, the editors provide comparative analyses of the cases reported and a special report is dedicated to how key decisions would be resolved under model European rules on tort law. The editors believe that the material gathered here may provide guidance for an organic convergence of the national legal systems in Europe. It constitutes the basis of an acquis commun that is infinitely richer (though also much more complex) than the rather bland and abstract concepts contained in national codifications, European legislation and modern model rulesMykolo Romerio universitetasPrivatinės teisės katedraVytauto Didžiojo universiteta

PPAR\gamma activation but not PPAR\gamma haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors

Background. Peroxisome proliferator-activated receptor-? (PPAR?) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPAR? on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs). Methods. PACs were isolated from bone marrow of 10¿12 weeks old, wild type, db/db and PPAR? heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 ?mol/L) or GW9662 (10 ?mol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model. Results. ECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPAR? activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells. Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPAR? and changed expression of PPAR?-regulated genes. Using normoglycemic PPAR?+/? mice we demonstrated that reduced expression of PPAR? does not influence neovascularization either in wound healing or in hind limb ischemia models. Conclusions. In summary, activation of PPAR? by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPAR? in diabetes does not impair angiogenesis