EDITOR'S PICK: Immunosuppressive drugs are a double-edged sword to type 1 diabetics
Type 1 diabetes is caused when immune cells attack and destroy the insulin producing beta-cells of the pancreas. Although insulin injections have changed the life of type I diabetics, they neither cure the disease nor prevent its severe complications. It was hoped that islet transplantation would provide a cure, however, transplant success is short-lived and accompanied by significant side effects. New data from Yuval Dor and colleagues at the Hebrew University-Hadassah Medical School, Jerusalem, have indicated that the immunosuppressive drugs used to prevent rejection of islet transplants suppress beta-cell regeneration in diabetic mice. As mentioned by the authors and discussed in the accompanying commentary by Klaus Kaestner from the University of Pennsylvania, Philadelphia, this raises the possibility that if immunosuppressive drugs that do not inhibit beta-cell regeneration can be identified successful regenerative islet transplantation might become a reality.
TITLE: Recovery from diabetes in mice by beta-cell regeneration
AUTHOR CONTACT:
Yuval Dor
The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Phone: 972-2-6757181; Fax: 972-2-6415848; E-mail yuvald@ekmd.huji.ac.il.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32959
ACCOMPANYING COMMENTARY
TITLE: Beta-cell transplantation and immunosuppression: can't live with it, can't live without it
AUTHOR CONTACT:
Klaus H. Kaestner
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8759; Fax: (215) 573-5892; E-mail: kaestner@mail.med.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33375
EDITOR'S PICK: It's a knock out: eIF4E-specific antisense oligonucleotides knock down cancer
A new study by Jeremy Graff and colleagues from Eli Lilly and Company has demonstrated the anti-cancer effect of a new therapeutic in a mouse model of human tumors and has spawned clinical trials to test the ability of this therapeutic to treat human cancers. As highlighted in the accompanying commentary by Celeste Simon and colleagues from the University of Pennsylvania, Philadelphia, if the therapeutic is as effective in clinical trials as it was in mice it will be useful for the treatment of a broad range of cancers.
The growth of many tumors is promoted by increased expression of the protein eIF4E, but no eIF4E-specific therapy has yet been developed. In this study, the intravenous administration of eIF4E-specific antisense oligonucleotides (ASOs) to mice bearing human tumors substantially inhibited tumor growth. Importantly, although these ASOs also decreased eIF4E expression in normal tissues, the function of the normal tissues analyzed was not compromised. The authors therefore suggest that tumor cells are more susceptible to decreased expression of eIF4E than normal cells, meaning that eIF4E-specific ASOs should not cause damage to normal tissues.
TITLE: Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity
AUTHOR CONTACT:
Jeremy R. Graff
Eli Lilly and Company, Indianapolis, Indiana, USA.
Phone: (317) 277-0220; Fax: (317) 277-3652; E-mail: graff_jeremy@lilly.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32044
ACCOMPANYING COMMENTARY
TITLE: Taking aim at translation for tumor therapy
AUTHOR CONTACT:
M. Celeste Simon
Abramson Family Cancer Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 746-5532; Fax: (215) 746-5511; E-mail: celeste2@mail.med.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33107
MICROBIOLOGY: New use as an antifungal agent for old drug
Infection with certain fungi results in mucormycosis, which is a lethal but rare fungal infection for which there are no good therapeutics. Now, Ashaf Ibrahim and colleagues at UCLA have shown that an iron-binding drug known as deferasirox substantially improved survival and decreased fungal burden in mice infected with Rhizopus oryzae, the most common cause of mucormycosis in humans. Furthermore, the effects of deferasirox were synergistic with liposomal ampohotericin B, which is currently used to treat individuals with mucormycosis. As deferasirox has recently been approved by the FDA to treat iron overload in individuals with transfusion-dependent anemias, the authors suggest that their study provides support for clinical trials investigating the potential of deferasirox as an adjunct therapy for mucormycosis.
TITLE: The iron chelator deferasirox protects mice from mucormycosis through iron starvation
AUTHOR CONTACT:
Ashraf S. Ibrahim
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Phone: (310) 222-6424; Fax: (310) 782-2016; E-mail: ibrahim@labiomed.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32338
CARDIOVASCULAR BIOLOGY: Antioxidant used in the clinic causes disease in mice
In a new study, Benjamin Gaston and colleagues from the University of Virginia School of Medicine, Charlottesville, have shown that chronic treatment of mice with a drug known as NAC, which is an antioxidant used commonly in the clinic, causes pulmonary arterial hypertension (in humans, pulmonary arterial hypertension leads to heart failure). This surprising observation raises questions about the long-term use of NAC in humans and provides researchers with a new mouse model of pulmonary hypertension that mimics the effects of chronic hypoxia. However, as Philip Marsden cautions in the accompanying commentary, further studies are required to determine whether chronic NAC therapy causes similar problems in humans.
TITLE: S-nitrosothiols signal hypoxia-mimetic vascular pathology
AUTHOR CONTACT:
Benjamin Gaston
University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Phone: (434) 924-1820; Fax: (434) 924-8388; E-mail: bmg3g@virginia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29444
ACCOMPANYING COMMENTARY
TITLE: Low-molecular-weight S-nitrosothiols and blood vessel injury
AUTHOR CONTACT:
Philip A. Marsden
St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada.
Phone: (416) 978-2441; Fax: (416) 978-8765; E-mail: p.marsden@utoronto.ca.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33136
CARDIOLOGY: The beta1-adrenergic receptor is two faced in the heart
New data generated by Howard Rockman and colleagues at Duke University Medical Center, have identified a new signaling pathway downstream of the beta1-adrenergic receptor in the heart that protects the muscle cells of the heart from dying. The potential clinical impact of these observations is discussed in the accompanying commentary by Stefan Englehardt from the University of Würzburg, Germany.
In the study, stimulation of the beta1-adrenergic receptor, in vitro in human and mouse cells and in vivo in mice, was shown to activate a beta-arrestin signaling pathway that required the G protein–coupled receptor kinases 5 and 6 and resulted in transactivation of EGFR. Signaling downstream of EGFR activation protected the heart muscle cells from the toxic effects of chronic signals from the beta1-adrenergic receptor transmitted through Gs-dependent adenylyl cyclase activation. The latter signals are associated with heart failure and so the authors suggest that drugs that block Gs-dependent adenylyl cyclase activation but activate beta-arrestin signaling might provide a new type of therapeutic for the prevention of heart failure.
TITLE: Beta-Arrestin–mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection
AUTHOR CONTACT:
Howard A. Rockman
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 668-2520; Fax: (919) 668-2524; E-mail: h.rockman@duke.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31901
ACCOMPANYING COMMENTARY
TITLE: Alternative signaling: cardiomyocyte beta1-adrenergic receptors signal through EGFRs
AUTHOR CONTACT:
Stefan Engelhardt
University of Würzburg, Würzburg, Germany..
Phone: 49-931-201-48710; Fax: 49-931-201-48123; E-mail: stefan.engelhardt@virchow.uni-wuerzburg.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33135
PHYSIOLOGY: How to enhance muscle function
Skeletal muscle is composed of two types of muscle fiber, slow and fast, which have different capabilities — slow fibers do not tire easily and are high endurance, whereas fast fibers tire easily and are low endurance. The relative amount of each fiber type is determined by muscle usage — exercise training causes fast fibers to become slow fibers, whereas inactivity that results in muscle atrophy (for example inactivity induced by spinal cord injury and unloading caused by space flight or tail suspension) causes slow fibers to become fast fibers. Two studies in mice appearing in the November issue of the Journal of Clinical Investigation have provided insight into the molecular mechanisms that regulate muscle function. As discussed in the accompanying commentary by David Glass from Novartis Institutes for BioMedical Research, these two studies provide much fodder for researchers looking to develop new therapeutics for the treatment of skeletal muscle diseases.
Eric Olson and colleagues from the University of Texas Southwestern Medical Center, Dallas, showed that in mice, proteins known as class II HDACs repress the activity of MEF2, which is required for the expression of genes that cause muscle fibers to be slow fibers. Furthermore, in slow fibers, class II HDACs were degraded by the ubiquitin proteasome system such that slow fiber identity was maintained. In the second study, Shin'ichi Takeda and colleagues from the National Center of Neurology and Psychiatry, Tokyo, showed that in mice, one mechanism by which tail suspension causes muscle atrophy is that it alters the function of a protein known as nNOS, which leads to the activation of Foxo3a, which, in turn, upregulates the expression of various atrophy-related genes. Importantly, pharmacological inhibition of nNOS attenuated muscle atrophy in the mice.
TITLE: Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers
AUTHOR CONTACT:
Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-1187; Fax: (214) 648-1196; E-mail: eric.olson@utsouthwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31960
RELATED MANUSCRIPT
TITLE: NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS
AUTHOR CONTACT:
Shin'ichi Takeda
National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Phone: 81-42-346-1720; Fax: 81-42-346-1750; E-mail: takeda@ncnp.go.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30654
ACCOMPANYING COMMENTARY
TITLE: Two tales concerning skeletal muscle
AUTHOR CONTACT:
David J. Glass
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Phone: (617) 871-7820; Fax: (617) 871-7049; E-mail: david.glass@novartis.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33379
IMMUNOLOGY: Coming unstuck: T cell persistently tethered to integrin ligands can't reach their goal
For immune cells known as T cells to be effective they must home to the site of an infection. Similarly, for T cells to inappropriately mount an immune response and cause diseases such as colitis they must traffic to the site of the disease. The different integrin adhesion molecules expressed T cells regulate the sites to which they can home; for example, integrin alpha4beta7 directs T cells to the gut. Modulating integrin adhesiveness might therefore provide a way to alter T cell homing for the treatment of pathogenic gut inflammation.
Motomu Shimaoka and colleagues at the CBR Institute for Biomedical Research, Boston, genetically modified the ADMIDAS regulatory domain of the beta7 chain of the integrin alpha4beta7 such that integrin alpha4beta7 was persistently in its active state. T cells in these mice failed to migrate properly because the integrin alpha4beta7 was persistently bound to its ligand MAdCAM-1. These mice therefore had fewer T cells in their gut. Furthermore, T cells from these mice had a reduced capacity to induce colitis. As discussed in the accompanying commentary by Ivor Douglas and Themistocles Dassopoulos, this demonstration of the importance of the ADMIDAS domain in controlling integrin de-adhesion is crucial for the future design of small molecules for the treatment chronic inflammatory conditions such as colitis.
TITLE: Aberrant activation of integrin alpha4beta7 suppresses lymphocyte migration to the gut
AUTHOR CONTACT:
Motomu Shimaoka
CBR Institute for Biomedical Research, Boston, Massachusetts, USA.
Phone: (617) 278-3272; Fax: (617) 278-3232; E-mail: shimaoka@cbrinstitute.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31570
ACCOMPANYING COMMENTARY
TITLE: Rheostat regulation of integrin-mediated leukocyte adhesion
AUTHOR CONTACT:
Ivor S. Douglas
University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.
Phone: (303) 436-5905; Fax: (303) 436-7249; E-mail: idouglas@dhha.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33376
PHYSIOLOGY: Too many proteins spoil the muscle
Skeletal and heart (cardiac) muscles are composed of muscle fibers that contain many myofibrils, the contractile unit of muscles. Myofibrils are, in turn, built of many repeating units known as sarcomeres. As the proteins of the sarcomere are therefore crucial for muscle contraction, their synthesis, assembly, and degradation are tightly regulated and defects in any of these result in muscle dysfunction (myopathy). Eric Olson and colleagues at the University of Texas Southwestern Medical Center, Dallas, have now shown that mice lacking two proteins, MuRF1 and MuRF3, develop skeletal muscle myopathy and hypertrophic cardiomyopathy because degradation of their sarcomere proteins by the ubiquitin proteasome system was reduced. Inhibitors of MuRF proteins have been proposed as potential therapeutics for the treatment of muscle atrophy but the evidence presented in this study indicates that care should be taken to develop agents that specifically target individual MuRFs if such an approach is not to cause adverse side effects.
TITLE: Myosin accumulation and striated muscle myopathy result from loss of muscle RING finger 1 and 3
AUTHOR CONTACT:
Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-1187; Fax: (214) 648-1196; E-mail: Eric.Olson@utsouthwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32827
IMMUNOLOGY: Identifying who keeps watch in the skin
New data provided by Michelle Lowes and colleagues at The Rockefeller University, New York, has provided a detailed characterization of the immune sentinel cells in the normal human skin. As discussed in the accompanying commentary by Frank Nestle and Brian Nickoloff, these studies are crucial if we are to further our understanding of chronic inflammatory skin diseases, such as psoriasis, and to enhance the efficacy of vaccinations.
Detailed analysis of normal human skin enabled the authors to define two distinct populations of immune sentinel cells in the skin. The first, which was characterized by expression of CD11c, BDCA-1, HLA-DR, and CD45 was found mostly in the upper dermis and was able to stimulate T cell activation. The second, which was characterized by expression of FXIIIA and CD163 was found throughout the dermis and was unable to stimulate T cell activation. These populations correspond to immunostimulatory myeloid DCs and macrophages, respectively.
TITLE: Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages
AUTHOR CONTACT:
Michelle A. Lowes
The Rockefeller University, New York, New York, USA.
Phone: (212) 327-7576; Fax: (212) 327-8353; E-mail: lowesm@rockefeller.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32282
ACCOMPANYING COMMENTARY
TITLE: Deepening our understanding of immune sentinels in the skin
AUTHOR CONTACT:
Brian J. Nickoloff
Loyola University Medical Center, Maywood, Illinois, USA.
Phone: (708) 327-3241; Fax: (708) 327-3239; E-mail: bnickol@lumc.edu.
Frank O. Nestle
King's College London School of Medicine, London, United Kingdom.
Phone: 44-20-7188-9038; Fax: 44-20- 7188-2585; E-mail: frank.nestle@kcl.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33349
PHYSIOLOGY: ATM banks two new functions
Ataxia-telangiectasia (A-T) is a fatal childhood disorder caused by mutations in the gene encoding ATM. ATM coordinates the cellular response to DNA damage and although many of the symptoms of A-T can be explained by the loss of this function, not all can. In a new study, Gerald Shadel and colleagues from Yale University have identified two additional functions for ATM that might contribute to the pathology of A-T.
Analysis of tissues from patients with A-T and mice lacking ATM indicated that ATM regulates the level of expression and/or stability of ribonucleotide reductase (RR), the enzyme that mediates the rate-limiting step in the de novo synthesis of deoxyribonucleoside triphosphates, the building blocks of RNA. ATM and RR were also required to maintain normal levels of mitochondrial DNA, which is important for maintaining normal functioning of the mitochondria. In addition to providing insight into the molecular mechanisms responsible for the symptoms of A-T, the authors suggested that this study indicates that inherited mitochondrial DNA–depletion syndromes in humans (a fatal class of diseases) might be caused by mutations in the genes encoding the RR subunits.
TITLE: Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis
AUTHOR CONTACT:
Gerald S. Shadel
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-2475; Fax: (203) 785-2628; E-mail: gerald.shadel@yale.edu.
Jacqueline E. Weaver
Yale University Office of Public Affairs, New Haven, Connecticut, USA.
Phone: (203) 432-8555; Fax: (203) 432-1323; E-mail: jacqueline.weaver@yale.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=31604
Journal
Journal of Clinical Investigation