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Gorr T.A.,Institute of Veterinary Physiology | Wichmann D.,Institute of Veterinary Physiology | Hu J.,Institute of Veterinary Physiology | Hermes-Lima M.,University of Brasilia | And 9 more authors.
Physiological and Biochemical Zoology | Year: 2010

Many invertebrates and ectothermic vertebrates successfully cope with a fluctuating supply of ambient oxygen - and consequently, a highly variable tissue oxygenation - through increasing their antioxidant barriers. During chronic deprivation of oxygen, however, the hypometabolic defense mode of the fruit fly Drosophila, the hypoxia-induced behavioral hypothermia of the crayfish Pacifastacus leniusculus, and the production of ethanol during anoxia by the crucian carp Carassius carassius all indicate that these animals are also capable of utilizing a suite of genetic and physiological defenses to survive otherwise lethal reductions in tissue oxygenation. Normally, much of an organism's gene response to hypoxia is orchestrated via the hypoxia-inducible transcription factor HIF. Recent developments expand our view of HIF function even further by highlighting regulatory roles for HIF in the hypometabolism of insects, in the molting and the normoxic immune response of crustaceans, and in the control - via the downstream effector gene erythropoietin - of the hypoxic ventilatory response and pulmonary hypertension in mammals. These and related topics were collectively presented by the authors in a symposium of the 2008 ICA-CBP conference at Mara National Reserve, Kenya, Africa. This synthesis article communicates the essence of the symposium presentations to the wider community. © 2010 by The University of Chicago. All rights reserved.


Barchiesi F.,University of Zürich | Lucchinetti E.,University of Alberta | Zaugg M.,University of Alberta | Ogunshola O.O.,Institute of Veterinary Physiology | And 11 more authors.
Hypertension | Year: 2010

2-Methoxyestradiol (2-ME; estradiol metabolite) inhibits vascular smooth muscle cell (VSMC) growth and protects against atherosclerosis and vascular injury; however, the mechanisms by which 2-ME induces these actions remain obscure. To assess the impact of 2-ME on biochemical pathways regulating VSMC biology, we used high-density oligonucleotide microarrays to identify differentially expressed genes in cultured human female aortic VSMCs treated with 2-ME acutely (4 hours) or long term (30 hours). Both single gene analysis and Gene Set Enrichment Analysis revealed 2-ME-induced downregulation of genes involved in mitotic spindle assembly and function in VSMCs. Also, Gene Set Enrichment Analysis identified effects of 2-ME on genes regulating cell-cycle progression, cell migration/adhesion, vasorelaxation, inflammation, and cholesterol metabolism. Transcriptional changes were associated with changes in protein expression, including inhibition of cyclin D1, cyclin B1, cyclin-dependent kinase 6, cyclin-dependent kinase 4, tubulin polymerization, cholesterol and steroid synthesis, and upregulation of cyclooxygenase 2 and matrix metalloproteinase 1. Microarray data suggested that 2-ME may activate peroxisome proliferator-activated receptors (PPARs) in VSMCs, and 2-ME has structural similarities with rosiglitazone (PPARγ agonist). However, our finding of weak activation and lack of binding of 2-ME to PPARs suggests that 2-ME may modulate PPAR-associated genes via indirect mechanisms, potentially involving cyclooxygenase 2. Indeed, the antimitogenic effects of 2-ME at concentrations that do not inhibit tubulin polymerization were blocked by the PPAR antagonist GW9662 and the cyclooxygenase 2 inhibitor NS398. Finally, we demonstrated that 2-ME inhibited hypoxia-inducible factor 1α. Identification of candidate genes that are positively or negatively regulated by 2-ME provides important leads to investigate and better understand the mechanisms by which 2-ME induces its vasoprotective actions. © 2010 American Heart Association, Inc.


Jacobs R.A.,Institute of Veterinary Physiology | Jacobs R.A.,University of Zürich | Diaz V.,Institute of Veterinary Physiology | Diaz V.,Technical University of Madrid | And 9 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

The etiology of mammalian senescence is suggested to involve the progressive impairment of mitochondrial function; however, direct observations of age-induced alterations in actual respiratory chain function are lacking. Accordingly, we assessed mitochondrial function via high-resolution respirometry and mitochondrial protein expression in soleus, quadricep, and lateral gastrocnemius skeletal muscles, which represent type 1 slow-twitch oxidative muscle (soleus) and type 2 fast-twitch glycolytic muscle (quadricep and gastrocnemius), respectively, in young (10-12 weeks) and mature (74-76 weeks) mice. Electron transport through mitochondrial complexes I and III increases with age in quadricep and gastrocnemius, which is not observed in soleus. Mitochondrial coupling efficiency during respiration through complex I also deteriorates with age in gastrocnemius and shows a tendency (p =. 085) to worsen in quadricep. These data demonstrate actual alterations in electron transport function that occurs with age and are dependent on skeletal muscle type. © 2013 The Author.


Centanin L.,University of Heidelberg | Gorr T.A.,Institute of Veterinary Physiology | Wappner P.,University of Buenos Aires
Journal of Insect Physiology | Year: 2010

The insect tracheal system is a continuous tubular network that ramifies into progressively thinner branches to provide air directly to every organ and tissue throughout the body. During embryogenesis the basic architecture of the tracheal system develops in a stereotypical and genetically controlled manner. Later, in larval stages, the tracheal system becomes plastic, and adapts to particular oxygen needs of the different tissues of the body. Oxygen sensing is mediated by specific prolyl-4-hydroxylases that regulate protein stability of the alpha subunit of oxygen-responsive transcription factors from the HIF family. Tracheal cells are exquisitely sensitive to oxygen levels, modulating the expression of hypoxia-inducible proteins that mediate sprouting of tracheal branches in direction to oxygen-deprived tissues. © 2009 Elsevier Ltd. All rights reserved.


Frebel H.,ETH Zurich | Nindl V.,Cantonal Hospital St Gallen | Schuepbach R.A.,University of Zürich | Braunschweiler T.,ETH Zurich | And 8 more authors.
Journal of Experimental Medicine | Year: 2012

The inhibitory programmed death 1 (PD-1)-programmed death ligand 1 (PD-L1) pathway contributesto the functional down-regulation of T cell responses during persistent systemic and local virus infections. The blockade of PD-1-PD-L1-mediated inhibition is considered as a therapeutic approach toreinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1-deficient mice develop fatal pathology during early systemic lympho- cytic choriomeningitis virus (LCMV) infection, suggesting a host protective role of T cell down-regulation. As the exact mechanisms of pathology development remained unclear, we set out to delineate in detail the underlying pathogenesis. Mice deficient in PD-1-PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell-mediated immunopathology early after systemic LCMV infection. In the absence of regulation viaPD-1, CD8 T cells killed infected vascular endothelial cells via perforin-mediated cytolysis, therebyseverely compromising vascular integrity. This resulted in systemic vascular leakage and a consequential collapse of the circulatory system. Our results indicate that the PD-1-PD-L1 pathway protectsthe vascular system from severe CD8 T cell-mediated damage during early systemic LCMV infection,highlighting a pivotal physiological role of T cell down-regulation and suggesting the potential development of immunopathological side effects when interfering with the PD-1-PD-L1 pathway during systemic virus infections. © 2012 Frebel et al.


Padrutt I.,Clinic for Small Animal Internal Medicine | Lutz T.A.,Institute of Veterinary Physiology | Reusch C.E.,Clinic for Small Animal Internal Medicine | Zini E.,Clinic for Small Animal Internal Medicine
Research in Veterinary Science | Year: 2015

Incretin analogues and inhibitors of the breakdown of endogenous incretins are antidiabetic drugs that increase β-cell proliferation and glucose-stimulated insulin secretion in rodents and humans. Objectives were to test whether exenatide, exenatide extended-release, and sitagliptin can be safely used in cats, to identify the most effective drug, and to test the effects of prolonged exenatide extended-release administration. Three cats each were given exenatide (0.2-2 μg/kg, q12h, subcutaneously, 5 days), exenatide extended-release (40-400 μg/kg, subcutaneously, once), and sitagliptin (1-10 mg/kg, q24h, orally, 5 days). Before and after treatment, glucose, insulin and glucagon areas under the curve (AUC) were assessed by meal response tests (MRT). Exenatide increased insulin AUC by 224%, 258%, 331% and 93%, exenatide extended-release by 127%, 169%, 178% and 95%, and sitagliptin by 32%, 69%, 62%, and 43%, respectively. The tested drugs are safe to use in cats and enhance insulin secretion. Incretin-based therapy may be beneficial in cats with diabetes mellitus. © 2014 Elsevier Ltd.


Martin L.,German Institute of Animal Nutrition | Lodemann U.,Institute of Veterinary Physiology | Bondzio A.,Free University of Berlin | Gefeller E.-M.,Institute of Veterinary Physiology | And 4 more authors.
Journal of Nutrition | Year: 2013

High dietary zinc concentrations are used to prevent or treat diarrhea in piglets and humans, but long-term adaptation to high zinc supply has yet not been assessed. Intestinal zinc uptake is facilitated through members of zinc transporter families SLC30 (ZnT) and SLC39 (ZIP). Whereas in rodents, regulation of zinc homeostasis at lowor adequate zinc supply has been described, such mechanisms are unclear in piglets. A total of 54 piglets were fed diets containing 57 [low dietary zinc (LZn)], 164 [normal dietary zinc (NZn)], or 2425 [high dietary zinc (HZn)]mg/kg drymatter zinc. After 4 wk, 10 piglets/group were killed and jejunal tissues taken for analysis of zinc transporters SLC30A1 (ZnT1), SLC30A2 (ZnT2), SLC30A5 (ZnT5), SLC39A4 (ZIP4), divalentmetal transporter 1 (DMT1), andmetallothionein-1 (MT).Weight gainwas higher (P < 0.05) in pigs fed HZn than in the LZn and NZn groups during the first 2wk. Food intake did not differ between groups. The digesta and jejunal tissue zinc concentrations were higher (P < 0.05) in the HZn pigs than in NZn and LZn pigs. Expression of ZnT1 was higher (P < 0.05) and ZIP4 lower (P < 0.05) in HZn pigs than in the 2 other groups, whereas expression of ZnT5 and DMT1 did not differ between treatments. Expression of ZnT2 was lower (P < 0.05) in the LZn group than in the HZn and NZn groups. ThemRNA expression and protein abundance of MT was higher (P < 0.05) in the HZn group than in the NZn and LZn groups. Studies with intestinal porcine cell line intestinal epithelial cell-J2 confirmed the dose-dependent downregulation of ZIP4 and upregulation of ZnT1 and MT (P < 0.05) with increasing zinc concentration within 24 h. In conclusion, high dietary zinc concentrations increase intracellular zinc, promote increased zinc export fromintestinal tissues into extracellular compartments, and decrease zinc uptake fromthe gut lumen. The adaptive process appears to be established within 24 h; however, it does not prevent tissue zinc accumulation. © 2013 American Society for Nutrition.


Eichelmann M.A.,University of Zürich | Fischer D.,University of Zürich | Heilmann M.,University of Zürich | Bernstorf Hydeskov H.,University of Zürich | And 19 more authors.
International Zoo Yearbook | Year: 2012

Previous reports in the literature indicate that primate species differ in their iron metabolism. Analyses were carried out of 229 serum samples of 18 different species, including marmosets, lemurs, woolly monkeys, colobines, macaques, baboons and great apes, for transferrin saturation (%TS), an indicator of iron absorption. In correspondence with our expectations based on the literature, lemurs and marmosets had significantly higher %TS values than great apes and macaques/baboons. The findings corroborate patterns previously described in individual studies, and underline that further efforts should be made to understand the reasons and consequences of these differences in iron metabolism. © 2012 The Author. International Zoo Yearbook © 2012 The Zoological Society of London.


Pappo O.,Beilinson Hospital | Ben-Ari Z.,Beilinson Hospital | Shevtsov E.,Beilinson Hospital | Shevtsov E.,Cardiac Research Laboratory | And 5 more authors.
Canadian Journal of Physiology and Pharmacology | Year: 2010

Ischemia-reperfusion injury (I/R) is the main cause of primary graft nonfunction. Our aim was to evaluate the effect of excessive versus acute administration of erythropoietin (EPO) in attenuating the hepatic injury induced by I/R in mice. The effect of segmental (70%) hepatic ischemia was evaluated in a transgenic mouse line with constitutive overexpression of human EPO cDNA and in wild-type (WT) mice. Mice were randomly allocated to 5 main experimental groups: (i) WT-sham, (ii) WT ischemia, (iii) WT ischemia + recombinant human erythropoietin (rhEPO), (iv) transgenic-sham, and (v) transgenic ischemia. The EPO-pretreated mice showed a significant reduction in liver enzyme levels and intrahepatic caspase-3 activity and fewer apoptotic hepatocytes (p < 0.05 for all) compared with the WT untreated I/R group. EPO decreased c-Jun N-terminal kinase (JNK) phosphorylation and nuclear factor-kB (NF-kB) expression during I/R. In transgenic I/R livers, baseline histology showed diffused hepatic injury, and no significant beneficial effect was noted between the WT untreated and the transgenic I/R mice. In conclusion, acute pretreatment with EPO in WT mice attenuated in vivo I/R liver injury. However, in excessive EPO overexpression, the initial liver injury abolished the beneficial effect of EPO. These findings have important implications for the potential use of acute EPO in I/R injury during liver transplantation.


Rozenberg I.,Institute Of Physiology Ir | Rozenberg I.,University of Zürich | Sluka S.H.M.,Institute Of Physiology Ir | Sluka S.H.M.,University of Zürich | And 21 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective-: Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive.Methods and results-: Apolipoprotein E-null (ApoE) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. Conclusion-: These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease. © 2010 American Heart Association, Inc.

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