Martin Hermann

University of Innsbruck, Innsbruck, Tyrol, Austria

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Publications (95)372.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes is associated with pancreatic α cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of α cell dysfunction are unknown.
    American Journal of Clinical Nutrition 11/2014; 100(5):1222-31. · 6.50 Impact Factor
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    ABSTRACT: Background: Mitochondrial reactive oxygen species (ROS) produced during early reperfusion are important triggers for the development of ischemia/ reperfusion injury (IRI) in the course of solid organ transplantation. However, antioxidants yielded little clinical benefit in the prevention of IRI, most likely because of the failure to timely and efficiently target to the site of ROS production and action. In our work we are pursuing strategies to limit or prevent the early increase in ROS by targeting intracellular signaling pathways. Cytosolic p66SHC, which translocates to the mitochondria under stress to oxidize cytochrome c , is one of the main sources of ROS under stress conditions. Gene ablation experiments in mice also confirmed its important role in the development of IRI. Here we identified pathways essential for the activation of p66SHC, which may be targeted for therapeutic purposes. Methods: HL-1 cardiomyocytes and mouse embryonic fibroblasts (MEFs) were exposed to hypoxia/reoxygenation (HR) or pro-oxidant treatment. Intracellular signaling was monitored by phosphorylation-specific antibodies. ROS were detected by MitoTracker Red CM-H2XRos, DCF-DA, or protein- based ROS probes in vivo phosphorylation of p66SHC was analyzed by mass spectrometry. Results: Using MEFs and HL-1 cardiomyocytes we failed to detect the previously reported PKCß-dependent phosphorylation of p66SHC on S36 and instead identified S139 as critical target under oxidative stress. In p66SHC- deficient MEFs reconstituted with the S139A mutant of p66SHC we observed significantly reduced ROS levels. Also MAPK activities (ERK, JNK, p38), p66SHC S36 phosphorylation and ROS production were increased under prooxidant treatment and HR. Inhibition of signaling through MAPKs with specific inhibitors showed a pronounced decrease in p66SHC S36 phosphor- ylation only for JNK, which also directly interacted with p66SHC. Moreover, JNK inhibition resulted in decreased ROS production and reduced DNA damage. We further confirmed JNK-dependent regulation of p66SHC S36 phosphorylation, ROS production and cell death using JNK 1, 2 deficient MEFs. Finally, the low ROS phenotype of JNK 1, 2 knockout MEFs was reversed by introducing p66SHC mutated in S36E. Conclusion: Interference with p66SHC activation by targeting upstream pathways (PKCß, JNK) thus may provide a therapeutic approach for decreas- ing damage to cells and organs during ischemia/reperfusion.
    AUSTROTRANSPLANT, Bad Ischl; 10/2014
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    ABSTRACT: The effect of cold ischemia (CI) in vascularized composite allotransplantation is unknown. We herein assess tissue-specific damage, acceptable CI time, and the effect of preservation solutions in a syngenic rat hindlimb transplant model.
    Transplantation 07/2014; · 3.78 Impact Factor
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    ABSTRACT: Prolonged Ischemia (I) times caused by organ procurement and transport are main contributors to a decrease in organ function, which is further enhanced during early reperfusion (R). This combined damage, referred to as ischemia-reperfusion injury (IRI), is a main contributor to delayed graft function, which leads to costly and lengthy follow-up treatments or even organ loss. Methods to monitor the status of a graft prior to transplantation are, therefore, highly desirable to optimize the clinical outcome. Here we propose the use of fine needle biopsies, which are analyzed by real time live confocal microscopy. Such a combination provides information about the functional and structural integrity of an organ within a few minutes. To confirm the feasibility of this approach, we obtained fine needle biopsies from rodent kidneys and exposed them to various stress conditions. Following the addition of a range of live stains, biopsies were monitored for mitochondrial function, cell viability and tissue integrity using confocal live cell imaging. Our data demonstrate that this procedure requires minimal time for sample preparation and data acquisition and is well suitable to record organ damage resulting from unphysiological stress. This article is protected by copyright. All rights reserved.
    Transplant International 04/2014; · 3.16 Impact Factor
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    ABSTRACT: Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects. Here we identified p38MAPKalpha as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKalpha signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death. These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.
    Cell Communication and Signaling 01/2014; 12(1):6. · 5.09 Impact Factor
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    ABSTRACT: Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation.
    PLoS ONE 01/2014; 9(11):e112570. · 3.53 Impact Factor
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    ABSTRACT: Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/lysosomal adaptor and MAPK and mTOR activator/regulator (LAMTOR) complex, thereby contributing to the signal transduction of the "extracellular signaling-regulated kinase" (ERK) and the "mammalian target of rapamycin" (mTOR) cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Since p14 participates in the regulation of endosomal trafficking, growth factor signaling and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knock out mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Dysregulation of the insulin-like growth factor (IGF) axis is implicated in the development of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common diseases affecting elderly males. PCa is the second leading cause of male-related cancer death in Western societies. Although distinct pathologies, BPH and PCa are both characterized by extensive stromal remodeling, in particular fibroblast-to-myofibroblast differentiation thought to be induced by elevated local production of transforming growth factor beta 1 (TGFβ1). We previously showed that TGFβ1-mediated fibroblast-to-myofibroblast differentiation of primary human prostatic stromal cells (PrSCs) resulted in dsyregulation of several components of the IGF axis, including induction of IGF binding protein 3 (IGFBP3). Using isoform-specific lentiviral-mediated knockdown, we demonstrate herein that IGFBP3 is essential for TGFβ1-mediated differentiation. Whilst recombinant human IGFBP3 alone was not sufficient to induce differentiation, IGFBP3 synergistically potentiated TGFβ1-mediated stromal remodeling predominantly via an IGF-independent mechanism. Consistent with these in vitro findings, IGFBP3 immunohistochemistry revealed elevated levels of IGFBP3 in the hyperplastic fibromuscular stroma of BPH specimens and in the tumor-adjacent stroma of high-grade PCa. Collectively, these data indicate that dysregulation of the stromal IGF axis, in particular elevated IGFBP3, plays a crucial role in fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma and indicate the therapeutic potential of inhibiting stromal remodeling and the resulting dysregulation of the stromal IGF axis as a novel strategy for the treatment of advanced PCa and BPH.
    Endocrinology 05/2013; · 4.72 Impact Factor
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    ABSTRACT: Lipocalin-2 (Lcn2) expression contributes to ischemia and reperfusion injury (IRI) by enhancing pro-inflammatory responses. The aim of this work was to elucidate the regulation of Lcn2 during hypoxia and its effects on the expression of key chemokines and adhesion molecules. Lcn2 wt and Lcn2(-/-) mice were used in a heterotopic heart transplantation model. Quantitative RT-PCR was applied for chemokine gene expression analysis. Reporter gene studies were used to elucidate the regulation of the Lcn2 promoter by hypoxia. HIF-1β expression led to a 2.4-fold induction of the Lcn2 promoter. Apart from an earlier onset of granulocyte infiltration in the Lcn2 wt setting after 2 h of reperfusion compared with the Lcn2(-/-) setting (P < 0.013), exogenous application of recombinant Lcn2 revealed a trend toward increase of granulocyte infiltration. Analyzed chemokines were expressed significantly higher in the Lcn2 wt setting at 2 h of reperfusion (P ≤ 0.05). The number of apoptotic cells observed in Lcn2(-/-) grafts was significantly higher than in the Lcn2 wt setting. Our results indicate that Lcn2 affects granulocyte infiltration in the reperfused graft by modulating the expression of chemokines, their receptors and the apoptotic rate.
    Transplant International 05/2013; · 3.16 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) generated by NADPH oxidases play an important role in cellular signal transduction regulating cell proliferation, survival and differentiation. NADPH oxidase 4 (Nox4) induces cellular senescence in human endothelial cells; however, intracellular targets for Nox4 remained elusive. Here we show that Nox4 induces mitochondrial dysfunction in human endothelial cells. Nox4 depletion induced alterations in mitochondrial morphology, stabilized mitochondrial membrane potential, and decreased production of hydrogen peroxide in mitochondria. High-resolution respirometry in permeabilized cells combined with native polyacrylamide gel electrophoresis demonstrated that Nox4 specifically inhibits the activity of mitochondrial electron transport chain complex I, and this was associated with a decreased concentration of complex I subunits. These data suggest a new pathway by which sustained Nox4 activity decreases mitochondrial function.
    Biochemical Journal 03/2013; · 4.65 Impact Factor
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    ABSTRACT: Islet transplantation is a valid treatment option for patients suffering from type 1 diabetes mellitus. To assure optimal islet cell quality, specialized islet isolation facilities have been developed. Utilization of such facilities necessitates transportation of islet cells to distant institutions for transplantation. Despite its importance, a clinically feasible solution for the transport of islets has still not been established. We here compare the functionality of isolated islets from C57BL/6 mice directly after the isolation procedure as well as after two simulated transport conditions, static versus rotation. Islet cell quality was assessed using real-time live confocal microscopy. In vivo islet function after syngeneic transplantation was determined by weight and blood sugar measurements as well as by intraperitoneal glucose tolerance tests. Vascularization of islets was documented by fluorescence microscopy and immunohistochemistry. All viability parameters documented comparable cell viability in the rotary group and the group transplanted immediately after isolation. Functional parameters assessed in vivo displayed no significant difference between these two groups. Moreover, vascularization of islets was similar in both groups. In conclusion, rotary culture conditions allows the maintenance of highest islet quality for at least 15 h, which is comparable to that of freshly isolated islets.
    BioMed research international. 01/2013; 2013:975608.
  • 36. Seminar für Chirurgische Forschung, Vienna, Austria; 11/2012
  • 26. Tagung der Österreichischen Gesellschaft für Transplantation, Transfusion und Genetik, Rust am Neusiedlersee, Austria; 10/2012
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    ABSTRACT: Tetrahydrobiopterin has been shown to efficiently abrogate ischemia reperfusion injury (IRI). However, it is unclear, whether its beneficial action relies on cofactor activity of one of the five known tetrahydrobiopterin-dependent reactions or on its antioxidative capacity. We therefore compared tetrahydrobiopterin with the pterin derivate tetrahydroneopterin (similar biochemical properties, but no nitric oxide synthase cofactor activity) and the antioxidants vitamin C and 5-methyltetrahydrofolate. Donor mice were pretreated with tetrahydrobiopterin, tetrahydroneopterin, vitamin C, or 5-methyltetrahydrofolate. Pancreatic grafts were subjected to 16-h cold ischemia time and implanted in syngeneic recipients. Untreated and nontransplanted animals served as controls. Following 2-h reperfusion, microcirculation was analyzed by intravital fluorescence microscopy. Graft damage was assessed by histology and nitrotyrosine immunostaining, and tetrahydrobiopterin levels were determined by HPLC. Recipient survival served as ultimate readout. Prolonged cold ischemia time resulted in microcirculatory breakdown. Only tetrahydrobiopterin pretreatment succeeded to preserve the capillary net, whereas all other compounds showed no beneficial effects. Along with increased intragraft tetrahydrobiopterin levels during recovery and implantation, only tetrahydrobiopterin pretreatment led to significant reduction of IRI-related parenchymal damage enabling recipient survival. These results show a striking superiority of tetrahydrobiopterin in preventing lethal IRI compared with related compounds and suggest nitric oxide synthases as treatment target.
    Transplant International 07/2012; 25(10):1084-1095. · 3.16 Impact Factor
  • 24th International Congress of the Transplantation Society, Berlin, Germany; 07/2012
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    ABSTRACT: The setup of an islet isolation facility designed along the rules of good manufacturing practice (GMP) is a technically challenging, cost and time intensive process. ( 1) Consequently, several institutions have decided to perform transplantation of islets isolated at another center with an already standing expertise. Such a solution includes the necessity to transport the isolated islets from the isolation to the transplantation facility. In spite of its importance, an ideal solution for the transport of the isolated human islets has still not been established. Here, we present an islet transport device suited to transport human islet cells under reproducible conditions and minimized cell stress. The transport simulation of the human islets was performed in a transfused "rotary transport system for islets" termed "ROTi." Besides measuring standard metabolic (LDH, lactate, glucose) and physical parameters (pH, dissolved oxygen and temperature), we used five different live stains in combination with real time live confocal microscopy to document islet quality parameters. As live stains we added tetramethylrhodamine methyl ester, cell permeant acetoxymethylester, propidium iodide, annexin-fitc and fluorescent wheat germ agglutinin, and assessed mitochondrial membrane potentials, calcium levels, cell death, apoptosis or cell morphology, respectively. We compared the viability of human islets after 24 h incubation in the ROTi device to an incubation simulating "standard" shipment of islets in 50 ml tubes. All cell viability parameters studied (mitochondrial membrane potentials, calcium content, apoptosis, cell death as well as cell morphology) documented a significantly better cell viability in the ROTi fraction compared with the simulated "standard" shipment fraction. Besides maintaining islet cell viability, the ROTi bears the advantage of a better reproducibility of islet transport conditions.
    Islets 03/2012; 4(2):152-7. · 1.55 Impact Factor
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    ABSTRACT: Despite recent advances in therapy, multiple myeloma, the second most common hematologic tumor in the Western world, is still incurable. Identification of substances that display a wide range of tumor-killing activities and target cancer-specific pathways constitute a basis for the development of novel therapies. In this study, we investigate the cytotoxic effect of the natural substance cnicin in multiple myeloma. Cnicin treatment reveals potent antiproliferative effects and induces cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells are unaffected. We show that activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. We provide evidence that Pim-2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. Thus, our data indicate that cnicin induces myeloma cell death via several pathways and reveals Pim-2 as a novel target. These findings provide a rational for further evaluation of cnicin as a new anti-tumor drug and underline the potential of sesquiterpene lactones in tumor therapy.
    Journal of Molecular Medicine 12/2011; 90(6):681-93. · 4.77 Impact Factor
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    ABSTRACT: The B lymphocyte adaptor molecule of 32 kDa (Bam32) is strongly induced during the maturation of dendritic cells (DC). Most known functions of Bam32 are related to the signaling of the B cell receptor for Ag. Because DC do not express receptors specific for Ags, we aim at characterizing the role of Bam32 in human monocyte-derived DC in this study. Our results show that binding of allogeneic T cells to mature DC causes accumulation of Bam32 on the contact sites and that this translocation is mimicked by Ab-mediated engagement of MHC class I. Silencing of Bam32 in mature monocyte-derived DC results in an enhanced proliferation of CD8(+) T cells in an Ag-specific T cell proliferation assay. Further studies identify galectin-1 as an intracellular binding partner of Bam32. Regulating immune responses via regulatory T cell (Treg) modulation is one of the many immunological activities attributed to galectin-1. Therefore, we assayed mixed leukocyte reactions for Treg expansion and found fewer Treg in reactions stimulated with DC silenced for Bam32 compared to reactions stimulated with DC treated with a nontarget control. Based on our findings, we propose a role for Bam32 in the signaling of MHC class I molecules in professional Ag-presenting DC for the regulation of CD8(+) T cell activation. It is distinct from that of MHC class I recognized by CD8(+) T cells leading to target [corrected] cell death. Thus, our data pinpoint a novel level of T cell regulation that may be of biological relevance.
    The Journal of Immunology 09/2011; 187(8):3972-8. · 5.52 Impact Factor
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    ABSTRACT: Pancreatic cancer (PaCa) is the fourth leading cause of cancer deaths in Western societies, with pancreatic ductal adenocarcinomas (PDACs) accounting for >90% of such cases. PDAC is a heterogeneous disease that includes a subset showing overexpression of the secreted glycoprotein Dickkopf-related protein 3 (Dkk-3), a protein shown to be downregulated in various cancers of different tissues. The biological function of Dkk-3 in this subset was studied using the Dkk-3 expressing PANC-1 cell line as a model for PDACs. The influence of Dkk-3 overexpression and knockdown on cellular differentiation and proliferation of PANC-1 was investigated. Confocal microscopy showed that Dkk-3 was expressed in a fraction of PANC-1 cells. While lentiviral-mediated overexpression of DKK3 did not alter cellular proliferation, knockdown of DKK3 resulted in significant reduction of cellular proliferation and concomitant induction of cell cycle inhibitors CDKN2B (p15INK4b), CDKN1A (p21CIP1) and CDKN1B (p27KIP1). In parallel, pancreatic epithelial cell differentiation markers AMY2A, CELA1, CTRB1, GCG, GLB1 and INS were significantly upregulated. PANC-1 cells differentiated using exendin-4 showed analogous induction of cell cycle inhibitors and differentiation markers. Thus, we conclude that Dkk-3 is required to maintain a highly dedifferentiated and consequently proliferative state in PANC-1, indicating a similar function in the Dkk-3 overexpressing subset of PDACs. Therefore, Dkk-3 represents a potential target for the treatment of Dkk-3-positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation.
    International Journal of Oncology 08/2011; 40(1):40-6. · 2.66 Impact Factor
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    ABSTRACT: Dickkopf (dkk) genes belong to the family of secreted wnt-inhibitors with conserved cysteine-rich domains. In contrast to the prototype dkk1, dkk3 does not modulate canonical Wnt/β-catenin signalling. Until now, neither functions nor interaction partners of dkk3 in lower vertebrates have been described. In this study we cloned two dkk3 homologues dkk3a(dkk3l) and dkk3b(dkk3) and a dkk1 homologue dkk1a of the zebrafish and studied their expression patterns during embryonic development in comparison to the known dkk1b gene. Moreover, mutants with defects in hedgehog signalling (smo), notch (mib) signalling, nodal signalling (Zoep) or retinoic acid synthesis (neckless) were analyzed for changes in dkk3 gene expression. In situ hybridization analyses showed a dynamic expression of dkk1a and dkk1b primarily in epidermal structures of the otic vesicle, lens, branchial arches and fin folds. While dkk1a was expressed mainly in deep tissues, dkk1b expression was mainly found in protrusions at the outer surface of the branchial arch epidermis. In contrast, dkk3 genes showed expression in different tissues. Strong signals for dkk3a(dkk3l) were present in various neuronal structures of the head, whereas dkk3b(dkk3) expression was restricted mainly to endocrine cells of the pancreas and to the brachial arches. In summary, both dkk3 genes display a unique and distinct expression pattern in late embryonic development, pointing to a specific role during neuronal and pancreatic cell differentiation.
    Gene Expression Patterns 08/2011; 11(8):491-500. · 1.64 Impact Factor

Publication Stats

1k Citations
372.67 Total Impact Points

Institutions

  • 2000–2014
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 1999–2012
    • Medizinische Universität Innsbruck
      • • Universitätsklinik für Visceral-, Transplantations- und Thoraxchirurgie
      • • Univ.-Klinik für Gynäkologie und Geburtshilfe
      Innsbruck, Tyrol, Austria
  • 1996–2010
    • Austrian Academy of Sciences
      • Institut für Biomedizinische Alternsforschung
      Vienna, Vienna, Austria