Current research articles in the field of Molecular Medicine published in online journals.
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On this page considered biochemistry journals:
Journal of Molecular Medicine - published by
Springer -
... covers all aspects of human biology and pathophysiology. The emphasis is on the unprecedented progress and precision now possible in the understanding, prevention, diagnosis and treatment of human diseases. The employment of molecular biology and gene technology has enhanced the understanding of human diseases and has created a new branch of research known as "molecular medicine".
Molecular Medicine - published by
The Feinstein Institute for Medical Research -
... publishes original research articles and expert commentaries on emerging concepts in the interdisciplinary field of molecular medicine.
Journal of Cellular and Molecular Medicine - published by
Blackwell -
... is an international journal publishing peer-reviewed articles dedicated to original research and concepts in all fields of cellular and molecular medicine.
Current research articles of the mentioned
journals:
Abstract Morbidity from degenerative aortic valve disease is increasing worldwide, concomitant with the ageing of the general population
and the habitual consumption of diets high in calories and cholesterol. Immunohistologic studies have suggested that the molecular
mechanism occurring in the degenerate aortic valve resembles that of atherosclerosis, prompting the testing of HMG CoA reductase
inhibitors (statins) for the prevention of progression of native and bioprosthetic aortic valve degeneration. However, the
effects of these therapies remain controversial. Although the molecular mechanisms underlying the onset of aortic valve degeneration
are largely unknown, research in this area is advancing rapidly. The signaling components involved in embryonic valvulogenesis,
such as Wnt, TGF-β1, BMP, and Notch, are also involved in the onset of aortic valve degeneration. Furthermore, investigations into extracellular
matrix remodeling, angiogenesis, and osteogenesis in the aortic valve have been reported. Having noted avascularity of normal
cardiac valves, we recently identified chondromodulin-I (chm-I) as a crucial anti-angiogenic factor. The expression of chm-I
is restricted to cardiac valves from late embryogenesis to adulthood in the mouse, rat, and human. In human degenerate atherosclerotic
valves, the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases and angiogenesis is observed
in the area of chm-I downregulation. Gene targeting of chm-I resulted in VEGF expression, angiogenesis, and calcification
in the aortic valves of aged mice, and aortic stenosis is detected by echocardiography, indicating that chm-I is a crucial
factor for maintaining normal cardiac valvular function by preventing angiogenesis. The present review focuses on the animal
models of aortic valve degeneration and recent studies on the molecular mechanisms underlying the onset of degenerative aortic
valve disease.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0400-9
Authors
Daihiko Hakuno, Keio University School of Medicine Department of Regenerative Medicine and Advanced Cardiac Therapeutics 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
Naritaka Kimura, Keio University School of Medicine Department of Regenerative Medicine and Advanced Cardiac Therapeutics 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
Masatoyo Yoshioka, Keio University School of Medicine Department of Regenerative Medicine and Advanced Cardiac Therapeutics 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
Keiichi Fukuda, Keio University School of Medicine Department of Regenerative Medicine and Advanced Cardiac Therapeutics 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
The severe hypermetabolic response following burn injury correlates with age and may be a major contributor to higher morbidity and mortality rates observed in adult burn patients compared with children.
Abstract Mutations of the DNA methyltransferase 3B (DNMT3B) gene have been detected in patients with immunodeficiency, centromere instability,
and facial anomalies (ICF) syndrome. Most of these mutations are clustered in its catalytic domain and thus lead to defective
DNA methylation. Nevertheless, the S270P mutation in the N-terminal PWWP (Pro-Trp-Trp-Pro) domain of the DNMT3B gene has prompted
questions as to how this mutation contributes to the development of ICF syndrome. In this study, we found that wild-type DNMT3B
is SUMOylated through covalent modification, whereas the S270P mutant interacts with SUMO-1 via non-covalent interaction.
The S270P mutation results in diffuse nucleus localization. Moreover, the S270P mutant fails to interact with PIAS1, a small
ubiquitin-related modifier (SUMO) E3 ligase, and causes the constitutive activation of nuclear factor-kappa B, which induces
the expression of interleukin 8. Collectively, our data demonstrate that the S270P mutation affects DNMT3B functions via specific,
non-covalent interaction with SUMO-1.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0392-5
Authors
Jinah Park, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Tae-You Kim, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Yeonjoo Jung, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Sang-Hyun Song, National Institutes of Health The Laboratory of Cellular and Development Biology, NIDDK Bethesda MD 20892 USA
Sung-Hak Kim, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Do-Youn Oh, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Seock-Ah Im, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Yung-Jue Bang, Cancer Research Institute National Research Laboratory for Cancer Epigenetics Seoul Korea
Abstract DNA hypermethylation and histone modifications are two critical players involved in epigenetic regulation and together play
an important role in silencing tumor-suppressor genes in all cancers, including breast cancer. One of the major challenges
facing breast cancer researchers is the problem of how to identify critical genes that are epigenetically silenced early in
cancer initiation as these genes provide potential early diagnostic and/or therapeutic targets for breast cancer management.
This review will focus on compelling evidence that normal Human Mammary Epithelial Cells (HMECs) that escape senescence in
culture mimic genetic and epigenetic events occurring in early breast cancer, and provide a valuable system to delineate the
early steps in epigenetic deregulation that often occur during transition of a normal breast cell to a premalignant cell.
In particular, this model system has been used to investigate the relationship between gene silencing, DNA methylation, histone
modifications, and polycomb association that may occur early in oncogenic transformation.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0386-3
Authors
Rebecca A. Hinshelwood, The Garvan Institute of Medical Research 384 Victoria St Darlinghurst NSW 2010 Australia
Susan J. Clark, The Garvan Institute of Medical Research 384 Victoria St Darlinghurst NSW 2010 Australia
Abstract Peripheral vascular disease (PVD) is a growing medical problem in Western societies and presents itself mainly in two different
clinical forms. Intermittent claudication is an early moderate manifestation, while patients with critical limb ischemia suffer
from severe muscle tissue loss or ulcers and are at high risk for limb amputation. Unfortunately, many patients cannot be
helped with currently available surgical or endovascular revascularization procedures because of the complex anatomy of the
vascular occlusion and/or the presence of other risk factors. Noninvasive stem cell therapy has been proposed as an alternative
for such patients. Although pioneering clinical experience with stem cell-related therapy seems promising, it is too early
for general clinical use of this technique, since many questions remain unanswered. Indeed, while questions about safety,
dose, and administration route/timing/frequency are the first ones to be addressed when designing a stem cell-based clinical
approach, there is accumulating evidence from recent (pre-)clinical studies that other issues may also be at stake. For instance,
the choice of stem cells to be used and its precise mechanism of action, the need/possibility for concurrent tissue regeneration
in case of irreversible tissue loss, the differentiation degree and specific vascular identity of the transplanted cells,
and the long-term survival of engrafted cells in the absence of a normal supportive tissue environment should be well considered.
Here, rather than presenting a comprehensive and extensive overview on the current literature on stem/progenitor cells and
revascularization, we highlight some of the outstanding issues emerging from the recent (pre-)clinical literature that may
codetermine the successful application of stem cells in a wide range of PVD patients in the future.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0394-3
Authors
Xabier L. Aranguren, Katholieke Universiteit Leuven (KULeuven) Center for Molecular and Vascular Biology Campus Gasthuisberg, Herestraat 49 3000 Leuven Belgium
Catherine M. Verfaillie, KULeuven Stamcel Instituut Campus Gasthuisberg, Herestraat 49 3000 Leuven Belgium
Aernout Luttun, Katholieke Universiteit Leuven (KULeuven) Center for Molecular and Vascular Biology Campus Gasthuisberg, Herestraat 49 3000 Leuven Belgium
Abstract We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology
of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized
by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology
on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies
suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and
fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain
cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective
vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ratio,
and uncoupled respiration when incubating P301L tau mitochondria either with oligomeric or fibrillar preparations of Aβ42.
Finally, we found that aging specifically increased the sensitivity of mitochondria to oligomeric Aβ42 damage indicating that
oligomeric and fibrillar Aβ42 are both toxic, but exert different degrees of toxicity.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0391-6
Authors
Anne Eckert, Psychiatric University Clinic Basel Neurobiology Laboratory Wilhelm Klein-Strasse 27 4025 Basel Switzerland
Susanne Hauptmann, University of Frankfurt am Main Department of Pharmacology, ZAFES, Biocenter Frankfurt am Main Germany
Isabel Scherping, University of Frankfurt am Main Department of Pharmacology, ZAFES, Biocenter Frankfurt am Main Germany
Jessica Meinhardt, Leibniz Institute for Age Research Jena Germany
Virginie Rhein, Psychiatric University Clinic Basel Neurobiology Laboratory Wilhelm Klein-Strasse 27 4025 Basel Switzerland
Stefan Dröse, University Hospital Frankfurt am Main Molecular Bioenergetics Group, Centre of Biological Chemistry and Excellence ‘Macromolecular Complexes’ Frankfurt am Main Germany
Ulrich Brandt, University Hospital Frankfurt am Main Molecular Bioenergetics Group, Centre of Biological Chemistry and Excellence ‘Macromolecular Complexes’ Frankfurt am Main Germany
Marcus Fändrich, Martin Luther University Halle-Wittenberg Max-Planck Research Unit for Enzymology of Protein Folding Halle Germany
Walter E. Müller, University of Frankfurt am Main Department of Pharmacology, ZAFES, Biocenter Frankfurt am Main Germany
Jürgen Götz, University of Sydney Alzheimer’s and Parkinson’s Disease Laboratory, Brain & Mind Research Institute Sydney Australia
Abstract Recruitment and retention of circulating progenitor cells at the site of injured or ischemic tissues facilitates adult neo-vascularization.
We hypothesized that cell therapy could modulate local neo-vascularization through the vascular endothelial growth factor
(VEGF)/stromal cell-derived factor-1 (SDF-1) axis and by paracrine effects on local endothelial cells. We isolated from rat
bone marrow a subset of multipotent adult progenitor cell-derived progenitor cells (MDPC). In vitro, MDPCs secreted multiple
cytokines related to inflammation and angiogenesis, including monocyte chemotactic protein-1, SDF-1, basic fibroblast growth
factor, and VEGF, and expressed the chemokine receptors CXCR4 and VEGFR1. To investigate in vivo properties, we transplanted
MDPCs into the ischemic hind limbs of rats. Elevated levels of the chemokine SDF-1 and colocalization of CD11b+ cells marked the initial phase of tissue remodeling after cell transplantation. Prolonged engraftment was observed in the
adventitial–medial border region of arterioles of ischemic muscles. However, engrafted cells did not differentiate into endothelial
or smooth muscle cells. Limb perfusion normalized 4 weeks after cell injection. Inhibition of SDF-1 reduced the engraftment
of transplanted cells and decreased endothelial cell proliferation. These findings suggest a two-stage model whereby transplanted
MDPCs modulate wound repair through recruitment of inflammatory cells to ischemic tissue. This is an important potential mechanism
for cell transplantation, in addition to the direct modulation of local vascular cells through paracrine mechanisms.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0390-7
Authors
Andrew Wragg, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Jason A. Mellad, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Leilani E. Beltran, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Mikhail Konoplyannikov, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Hong San, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Sherry Boozer, Athersys Cleveland OH 44115 USA
Robert J. Deans, Athersys Cleveland OH 44115 USA
Anthony Mathur, Barts and the London William Harvey Research Institute London EC1M 6BQ UK
Robert J. Lederman, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Jason C. Kovacic, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Manfred Boehm, National Institutes of Health Translational Medicine Branch, National Heart, Lung, and Blood Institute Building 10-CRC, Room 5-3132 Bethesda MD 20817 USA
Christmas out of season: who is Kris Kringle and what has he wrought?
Content Type Journal Article
Category Clinical Implications
DOI 10.1007/s00109-008-0389-0
Authors
Friedrich C. Luft, Charité Universitary Medicine Experimental and Clinical Research Center, Campus Berlin-Buch Robert-Rössle-Straße 10 13122 Berlin-Buch Germany
Abstract Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences
in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse
aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but
with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated
genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes
of hypertrophy were similarly upregulated in both sexes (α-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial
function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase)
had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular
matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFβ2,
all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification,
female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed
the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity
and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences
could contribute to subsequent sex differences in cardiac function and HF.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0385-4
Authors
Henning Witt, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Carola Schubert, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Juliane Jaekel, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Daniela Fliegner, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Adam Penkalla, Charité-Universitaetsmedizin Berlin Center for Cardiovascular Research (CCR) Hessische Str. 3-4 10115 Berlin Germany
Klaus Tiemann, Universitaetsklinikum Bonn Medizinische Klinik und Polyklinik II Sigmund-Freud-Str. 25 53105 Bonn Germany
Joerg Stypmann, Universitaetsklinikum Bonn Medizinische Klinik und Polyklinik II Sigmund-Freud-Str. 25 53105 Bonn Germany
Stefan Roepcke, Max-Planck-Institute for Molecular Genetics Berlin Ihnestr. 63-73 14195 Berlin Germany
Sebastian Brokat, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Shokoufeh Mahmoodzadeh, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Eva Brozova, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Mercy M. Davidson, Columbia University College of Physicians and Surgeons New York NY USA
Patricia Ruiz Noppinger, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Christian Grohé, Universitaetsklinikum Bonn Medizinische Klinik und Polyklinik II Sigmund-Freud-Str. 25 53105 Bonn Germany
Vera Regitz-Zagrosek, Charité-Universitaetsmedizin Berlin Berlin Institute of Gender in Medicine (GiM) Luisenstraße 65 10117 Berlin Germany
Abstract Through genome-wide association studies, we have recently identified seven novel loci that confer a substantial increase in
risk for coronary artery disease (CAD). Elucidating the mechanisms by which these loci affect CAD risk could have important
clinical utility. Here, we investigated whether these loci act through mechanisms involving traditional cardiovascular risk
factors. We genotyped 2,037 adult individuals from 520 nuclear families characterised for body mass index, waist-hip ratio,
24-h ambulatory blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose for the lead single nucleotide
polymorphisms (SNPs) in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The CAD-associated risk allele A of rs599839
(allele frequency 0.78) was associated with a 0.17-mmol/l (95% CI 0.10 to 0.24 mmol/l) higher serum cholesterol level per
allele copy (P = 3.84 × 10−6). The association of the A allele with higher total cholesterol was confirmed in an independent cohort (n = 847) of healthy adults (P = 1.0 × 10−4) and related to an effect on low-density lipoprotein (LDL) cholesterol (P = 8.56 × 10−5). An association of rs599839 with LDL cholesterol was also shown in 1,090 cases with myocardial infarction (P = 0.0026). None of the other variants showed a strong association with the measured cardiovascular risk factors, suggesting
that these loci act through other mechanisms. However, the novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. The findings support further
investigation of the role of these genes in cholesterol metabolism and coronary risk.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0387-2
Authors
Nilesh J. Samani, University of Leicester Department of Cardiovascular Sciences Clinical Sciences Wing, Glenfield Hospital, Groby Road Leicester LE3 9QP UK
Peter S. Braund, University of Leicester Department of Cardiovascular Sciences Clinical Sciences Wing, Glenfield Hospital, Groby Road Leicester LE3 9QP UK
Jeanette Erdmann, Universität zu Lübeck Medizinische Klinik II Lübeck Germany
Anika Götz, Universität zu Lübeck Institut für Medizinische Biometrie und Statistik Lübeck Germany
Maciej Tomaszewski, University of Leicester Department of Cardiovascular Sciences Clinical Sciences Wing, Glenfield Hospital, Groby Road Leicester LE3 9QP UK
Patrick Linsel-Nitschke, Universität zu Lübeck Medizinische Klinik II Lübeck Germany
Cother Hajat, University of Leicester Department of Health Sciences and Genetics Leicester UK
Massimo Mangino, University of Leicester Department of Cardiovascular Sciences Clinical Sciences Wing, Glenfield Hospital, Groby Road Leicester LE3 9QP UK
Christian Hengstenberg, Universität Regensburg Klinik und Poliklinik für Innere Medizin II Regensburg Germany
Klaus Stark, Universität Regensburg Klinik und Poliklinik für Innere Medizin II Regensburg Germany
Andreas Ziegler, Universität zu Lübeck Institut für Medizinische Biometrie und Statistik Lübeck Germany
Mark Caulfield, Queen Mary’s School of Medicine and Dentistry Pharmacology and The Genome Centre, Barts and The London London UK
Paul R. Burton, University of Leicester Department of Health Sciences and Genetics Leicester UK
Heribert Schunkert, Universität zu Lübeck Medizinische Klinik II Lübeck Germany
Martin D. Tobin, University of Leicester Department of Health Sciences and Genetics Leicester UK
Abstract Spinal muscular atrophy (SMA) is a progressive disease involving the degeneration of motor neurons with no currently available
treatment. While valproic acid (VPA) is a potential treatment for SMA, its therapeutic mechanisms are still controversial.
In this study, we investigated the mechanisms of action of VPA in the treatment of type III-like SMA mice. SMA and wild-type
mice were treated with VPA from 6 to 12 months and 10 to 12 months of age, respectively. Untreated SMA littermates and age-matched
wild-type mice were used for comparison. VPA-treated SMA mice showed better motor function, larger motor-evoked potentials,
less degeneration of spinal motor neurons, less muscle atrophy, and better neuromuscular junction innervation than non-treated
SMA mice. VPA elevated SMN protein levels in the spinal cord through SMN2 promoter activation and probable restoration of correct splicing of SMN2 pre-messenger RNA. VPA also increased levels of anti-apoptotic factors, Bcl-2 and Bcl-xL, in spinal neurons. VPA probably induced neurogenesis and promoted astrocyte proliferation in the spinal cord of type III-like
SMA mice, which might contribute to therapeutic effects by enhancing neuroprotection. Through these effects of elevation of
SMN protein level, anti-apoptosis, and probable neuroprotection, VPA-treated SMA mice had less degeneration of spinal motor
neurons and better motor function than untreated type III-like SMA mice.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0388-1
Authors
Li-Kai Tsai, National Taiwan University Hospital and National Taiwan University College of Medicine Department of Neurology Taipei 100 Taiwan
Ming-Shiun Tsai, Da-Yeh University Department of Bioindustry Technology Dacun Changhua 515 Taiwan
Chen-Hung Ting, Academia Sinica Institute of Molecular Biology Nankang Taipei 115 Taiwan
Hung Li, Academia Sinica Institute of Molecular Biology Nankang Taipei 115 Taiwan
Abstract Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological
syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of
malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host’s ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded
by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates
the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The
protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during
the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a
central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious
effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0368-5
Authors
Ana Ferreira, Instituto Gulbenkian de Ciência 2780–156 Oeiras Portugal
József Balla, University of Debrecen Departments of Medicine and Neonatology, Medical and Health Science Center 4032 Debrecen Hungary
Viktória Jeney, University of Debrecen Departments of Medicine and Neonatology, Medical and Health Science Center 4032 Debrecen Hungary
György Balla, University of Debrecen Departments of Medicine and Neonatology, Medical and Health Science Center 4032 Debrecen Hungary
Miguel P. Soares, Instituto Gulbenkian de Ciência 2780–156 Oeiras Portugal
Abstract Stem cells are self-renewing multipotent progenitors with the broadest developmental potential in a given tissue at a given
time. Normal stem cells in the adult organism are responsible for renewal and repair of aged or damaged tissue. Adult stem
cells are present in virtually all tissues and during most stages of development. In this review, we introduce the reader
to the basic information about the field. We describe selected stem cell isolation techniques and stem cell markers for various
stem cell populations. These include makers for endothelial progenitor cells (CD146/MCAM/MUC18/S-endo-1, CD34, CD133/prominin,
Tie-2, Flk1/KD/VEGFR2), hematopoietic stem cells (CD34, CD117/c-Kit, Sca1), mesenchymal stem cells (CD146/MCAM/MUC18/S-endo-1,
STRO-1, Thy-1), neural stem cells (CD133/prominin, nestin, NCAM), mammary stem cells (CD24, CD29, Sca1), and intestinal stem
cells (NCAM, CD34, Thy-1, CD117/c-Kit, Flt-3). Separate section provides a concise summary of recent clinical trials involving
stem cells directed towards improvement of a damaged myocardium. In the last part of the review, we reflect on the field and
on future developments.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0383-6
Authors
Sabine Hombach-Klonisch, University of Manitoba Department of Human Anatomy and Cell Science Winnipeg Canada
Soumya Panigrahi, University of Manitoba Department of Physiology Winnipeg Canada
Iran Rashedi, University of Manitoba Manitoba Institute of Cell Biology, CancerCare Manitoba Winnipeg Manitoba Canada R3E 0V9
Anja Seifert, University of Manitoba Department of Human Anatomy and Cell Science Winnipeg Canada
Esteban Alberti, CIREN Department of Neurobiology, International Center of Neurological Restoration Havana Cuba
Paola Pocar, University of Milan Department of Animal Science, Faculty of Veterinary Medicine Milan Italy
Maciej Kurpisz, Polish Academy of Science Institute of Human Genetics Poznan Poland
Klaus Schulze-Osthoff, University of Duesseldorf Institute of Molecular Medicine Duesseldorf Germany
Andrzej Mackiewicz, Poznan University of Medical Sciences, and Great-Poland Cancer Center Department of Cancer Immunology Poznan Poland
Marek Los, BioApplications Enterprises Winnipeg Manitoba Canada
“Mollie Medcast,” a biweekly podcast, written and produced by Associate Editor Margot Gallowitsch -Puerta, includes brief audio summaries of recent articles published by Molecular Medicine. "Mollie Medcast" is available on our website atwww.molmed.org as well as from iTunes.
Episode 27: “If You Give A Rat A Cookie”, “PPARγ Ligands in Prostate Cancer”, and “ALI Pathogenesis”, a review paper dealing with acute lung injury
“Mollie Medcast,” a biweekly podcast, written and produced by Associate Editor Margot Gallowitsch -Puerta, includes brief audio summaries of recent articles published by Molecular Medicine. "Mollie Medcast" is available on our website atwww.molmed.org as well as from iTunes.
“Silencing Hepatocellular Carcinoma,” also, “Remodel Your Walls With SM22α,” and our Review And Asses paper or RNA paper for this episode “Aggregating Alzheimer’s And Parkinson’s.”
Continuing on the road to health: a short history of the Charité–universitätsmedizin Berlin from a plague house in the past to a medical school with a future
Content Type Journal Article
Category Editorial
DOI 10.1007/s00109-008-0382-7
Authors
Ernst Peter Fischer, Mozartstr. 10 78464 Konstanz Germany
Abstract Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features and is frequently caused by hypomethylation
(epimutation) of the H19-DMR. Although molecular and clinical studies have extensively been performed for SRS patients themselves, such studies have
not been carried out for placentas. We identified 20 epimutation-positive and 40 epimutation-negative Japanese SRS patients
and obtained placental weight data from 12 epimutation-positive and ten epimutation-negative patients and paraffin-embedded
placental tissues for molecular and histological examinations from three epimutation-positive and two epimutation-negative
patients. Methylation patterns were comparable between leukocytes and placentas in both epimutation-positive and epimutation-negative
patients. Epimutations resulted in virtually no IGF2 expression and biallelic slight H19 expression in the leukocytes and obviously reduced IGF2 expression of paternal origin and nearly normal H19 expression of maternal origin in the placentas. Epimutation-positive patients had characteristic body phenotype and small
placentas with hypoplastic chorionic villi, and epimutation-negative patients had somewhat small placentas with hypoplastic
chorionic villi or massive infarction. Furthermore, significant correlations were identified between the H19-DMR methylation index and the body and placental sizes and between the placental weight and the body size in the epimutation-positive
patients, whereas such correlations were not detected for the head circumference. These results suggest (1) characteristic
phenotype and reduced IGF2 expression in the epimutation-positive placentas; (2) similarities and differences in the epigenetic control of the IGF2–H19 domain between leukocytes and placentas; (3) a positive role of the IGF2 expression level, as reflected by the methylation index, in the determination of body and placental growth in epimutation-positive
patients, except for the brain where IGF2 is expressed biallelically; (4) involvement of placental dysfunction in prenatal growth failure; and (5) relevance of both
(epi)genetic factor(s) and environmental factor(s) to SRS in epimutation-negative patients.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0377-4
Authors
Kazuki Yamazawa, National Research Institute for Child Health and Development Department of Endocrinology and Metabolism Tokyo Japan
Masayo Kagami, National Research Institute for Child Health and Development Department of Endocrinology and Metabolism Tokyo Japan
Toshiro Nagai, Dokkyo Medical University Koshigaya Hospital Department of Pediatrics Koshigaya Japan
Tatsuro Kondoh, Nagasaki University Graduate School of Biomedical Sciences Department of Pediatrics Nagasaki Japan
Kazumichi Onigata, Gunma University Graduate School of Medicine Department of Pediatrics and Developmental Medicine Maebashi Japan
Katsuhiro Maeyama, Saitama City Hospital Department of Pediatrics Saitama Japan
Tomonobu Hasegawa, Keio University School of Medicine Department of Pediatrics Tokyo Japan
Yukihiro Hasegawa, Tokyo Metropolitan Kiyose Children’s Hospital Endocrinology and Metabolism Unit Kiyose Japan
Toshio Yamazaki, Fujita Health University Department of Pediatrics, School of Medicine Toyoake Japan
Seiji Mizuno, Aichi Human Service Center Department of Pediatrics, Central Hospital Kasugai Japan
Yoko Miyoshi, Osaka University Graduate School of Medicine Department of Pediatrics Suita Japan
Shinichiro Miyagawa, National Hospital Organization Kure Medical Center Department of Pediatrics Kure Japan
Reiko Horikawa, National Center for Child Health and Development Division of Endocrinology and Metabolism Tokyo Japan
Kentaro Matsuoka, National Center for Child Health and Development Division of Pathology Tokyo Japan
Tsutomu Ogata, National Research Institute for Child Health and Development Department of Endocrinology and Metabolism Tokyo Japan
Abstract Genomic insertion of a functional gene together with suitable transcriptional regulatory elements is often required for long-term
therapeutical benefit in gene therapy for several genetic diseases. A variety of integrating vectors for gene delivery exist.
Some of them exhibit random genomic integration, whereas others have integration preferences based on attributes of the targeted
site, such as primary DNA sequence and physical structure of the DNA, or through tethering to certain DNA sequences by host-encoded
cellular factors. Uncontrolled genomic insertion bears the risk of the transgene being silenced due to chromosomal position
effects, and can lead to genotoxic effects due to mutagenesis of cellular genes. None of the vector systems currently used
in either preclinical experiments or clinical trials displays sufficient preferences for target DNA sequences that would ensure
appropriate and reliable expression of the transgene and simultaneously prevent hazardous side effects. We review in this
paper the advantages and disadvantages of both viral and non-viral gene delivery technologies, discuss mechanisms of target
site selection of integrating genetic elements (viruses and transposons), and suggest distinct molecular strategies for targeted
gene delivery.
Content Type Journal Article
Category Review
DOI 10.1007/s00109-008-0381-8
Authors
Katrin Voigt, Max Delbrück Center for Molecular Medicine Robert-Rössle Strasse 10 13092 Berlin Germany
Zsuzsanna Izsvák, Max Delbrück Center for Molecular Medicine Robert-Rössle Strasse 10 13092 Berlin Germany
Zoltán Ivics, Max Delbrück Center for Molecular Medicine Robert-Rössle Strasse 10 13092 Berlin Germany
Abstract Imprinting analyses of IGF2 and H19, loss of heterozygosity (LOH) analyses of IGF2R and CTCF and Helicobacter pylori detection, were performed on 35 human laryngeal squamous cell carcinomas (LSCC). Forty-six percent of the tumors were heterozygous
for IGF2, and 54% were informative for the H19. Biallelic expression of IGF2 was observed in 33% (5 out of 15) of the tumors and in 27% (4 out of 15) of adjacent non-tumorous laryngeal tissues. H19 loss of imprinting (LOI) was observed in 24% (4 out of 17) of the tumors. For IGF2R and CTCF, 71% (25 out of 35) and 50% (17/34), respectively, of the samples were heterozygous, and LOH was detected in 12% (3 out of
25) and 6% (1 out of 17), respectively, of the tumors. H. pylori was found in 26% (9/35) of these tumors. Among them, four were informative for the imprinting analysis. The presence of H. pylori had no effect on IGF2/H19 imprinting. Only the H. pylori detection was further broadened with an additional 47 laryngeal tumors, resulting in a total final positivity of close to
16% (13 out of 82). This study represents the largest comprehensive IGF2/H19 imprinting study done to date on well-defined samples of human laryngeal carcinomas and corresponding non-tumorous tissue.
For the first time, the analyses of IGF2/H19 imprinting have been broadened with LOH analyses of IGF2R and CTCF, with both of these genes acting as modulators of IGF2 and H19 activity. Although there were indications that H. pylori may be present in LSCC, we are the first to show its presence in LSCC by two direct techniques: Giemsa staining and nested-PCR.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0369-4
Authors
Ivana Grbesa, Rudjer Boskovic Institute Laboratory of Molecular Pathology, Division of Molecular Medicine Zagreb Croatia
Marino Marinkovic, Rudjer Boskovic Institute Laboratory of Molecular Pathology, Division of Molecular Medicine Zagreb Croatia
Mirko Ivkic, Sestre milosrdnice University Hospital Department of Otorhinolaryngology and Head and Neck Surgery Zagreb Croatia
Bozo Kruslin, Sestre milosrdnice University Hospital Ljudevit Jurak Department of Pathology Zagreb Croatia
Renata Novak-Kujundzic, Rudjer Boskovic Institute Laboratory of Molecular Pathology, Division of Molecular Medicine Zagreb Croatia
Boris Pegan, Sestre milosrdnice University Hospital Department of Otorhinolaryngology and Head and Neck Surgery Zagreb Croatia
Ozren Bogdanovic, Rudjer Boskovic Institute Laboratory of Molecular Pathology, Division of Molecular Medicine Zagreb Croatia
Vladimir Bedekovic, Sestre milosrdnice University Hospital Department of Otorhinolaryngology and Head and Neck Surgery Zagreb Croatia
Koraljka Gall-Troselj, Rudjer Boskovic Institute Laboratory of Molecular Pathology, Division of Molecular Medicine Zagreb Croatia
Abstract Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue
remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated
in activation–inactivation of growth factors that play an important role in wound healing, including heparin-binding epidermal
growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression
of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin, based on microarrays
of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction
(RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal
for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations
that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence
of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12−/− or wild-type (WT) mice were used to quantify keratinocyte migration out of the explants over a period of 7 days. We found
a statistically significant increase in the migration of ADAM12−/− keratinocytes compared to WT control (p = 0.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds and the increased migration of keratinocytes
in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression
of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration and that topical ADAM12
inhibitors may therefore prove useful for the treatment of chronic wounds.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0353-z
Authors
Asheesh Harsha, Hospital for Special Surgery at Weill Medical College of Cornell University Arthritis and Tissue Degeneration Program New York NY USA
Olivera Stojadinovic, Hospital for Special Surgery at Weill Medical College of Cornell University Tissue Repair Lab, Tissue Engineering, Repair and Regeneration Program 535 E 70th Street New York NY 10021 USA
Harold Brem, Columbia University College of Physicians and Surgeons Wound Healing Program, Department of Surgery New York NY USA
Atsuko Sehara-Fujisawa, Kyoto University Graduate School of Medicine Department of Molecular Oncology Kyoto Japan
Ulla Wewer, University of Copenhagen Department of Biomedical Sciences Copenhagen Denmark
Cynthia A. Loomis, New York University School of Medicine New York NY USA
Carl P. Blobel, Hospital for Special Surgery at Weill Medical College of Cornell University Arthritis and Tissue Degeneration Program New York NY USA
Marjana Tomic-Canic, Hospital for Special Surgery at Weill Medical College of Cornell University Tissue Repair Lab, Tissue Engineering, Repair and Regeneration Program 535 E 70th Street New York NY 10021 USA
Abstract Mesenchymal stem cells (MSCs) can contribute to tissue repair by actively migrating to sites of tissue injury. However, the
cellular and molecular mechanisms of MSC recruitment are largely unknown. The nuclear factor (NF)-κB pathway plays a pivotal
role in regulating genes that influence cell migration, cell differentiation, inflammation, and proliferation. One of the
major cytokines released at sites of injury is tumor necrosis factor-α (TNF-α), which is known to be a key regulator of the
NF-κB pathway. Therefore, we hypothesized that TNF-α may lead to MSC invasion and proliferation by activation of the NF-κB
pathway. TNF-receptor 1 and 2, NF-κB (p65), and IκB kinase 2 (IKK-2) are expressed in human MSCs (hMSCs). Stimulation of hMSCs
with TNF-α caused a p65 translocation from the cytoplasm to nucleoplasm but did not change the expression profile of MSC markers.
TNF-α strongly augmented the migration of hMSCs through the human extracellular matrix. Using lentiviral gene transfer, overexpressing
a dominant-negative mutant of IKK-2 (dn-IKK-2) significantly blocked this effect. NF-κB target genes associated with migration
(vascular cell adhesion molecule-1, CD44, and matrix metalloproteinase 9) were upregulated by TNF-α stimulation and blocked
by dn-IKK-2. Moreover, using the bromodeoxyuridine assay, we showed that the inhibition of the NF-κB pathway caused a significant
reduction in the basal proliferation rate. TNF-α stimulated the proliferation of hMSCs, whereas overexpression of dn-IKK-2
significantly blocked this effect. TNF-α led to the upregulated expression of the proliferation-associated gene cyclin D1.
In conclusion, we demonstrated that the NF-κB pathway components, p65 and IKK-2, are expressed in hMSCs. Our data provide
evidence that this signal transduction pathway is implicated in TNF-α-mediated invasion and proliferation of hMSCs. Therefore,
hMSC recruitment to sites of tissue injury may, at least in part, be regulated by the NF-κB signal transduction pathway.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0378-3
Authors
Wolfgang Böcker, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Denitsa Docheva, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Wolf Christian Prall, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Virginia Egea, University of Munich (LMU) Division of Clinical Chemistry and Biochemistry, Department of Surgery Munich Germany
Emmanouil Pappou, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Oliver Roßmann, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Cvetan Popov, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Wolf Mutschler, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Christian Ries, University of Munich (LMU) Division of Clinical Chemistry and Biochemistry, Department of Surgery Munich Germany
Matthias Schieker, University of Munich (LMU) Experimental Surgery and Regenerative Medicine, Department of Surgery Nussbaumstrasse 20 80336 Munich Germany
Abstract The combination of inhaled corticosteroids and long-acting β2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated
that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte.
In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils.
Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase
and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP
kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased
expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression
of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP,
or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production
of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of
the GR to the nucleus. This leads eventually to suppression of both the NF-κB and MAPK pathways and, hence, to less IL-8 production
by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.
Content Type Journal Article
Category Original Article
DOI 10.1007/s00109-008-0360-0
Authors
Esmaeil Mortaz, Utrecht University Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences P.O. Box 80082 3508 TB Utrecht The Netherlands
Mehdi Vaezi Rad, Utrecht University Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences P.O. Box 80082 3508 TB Utrecht The Netherlands
Malcolm Johnson, GlaxoSmithKline Respiratory Science Greenford Middlesex UK
Danielle Raats, Utrecht University Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences P.O. Box 80082 3508 TB Utrecht The Netherlands
Frans P. Nijkamp, Utrecht University Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences P.O. Box 80082 3508 TB Utrecht The Netherlands
Gert Folkerts, Utrecht University Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences P.O. Box 80082 3508 TB Utrecht The Netherlands
