EDITOR’S PICK: Drug blocks lethal motor-neuron disease in mice
Spinal muscular atrophy (SMA) is an inherited motor-neuron disease that, in its most severe form, leads to death before 2 years of age and for which there is no treatment. It is caused by mutations in the gene SMN1 that prevent SMN1 producing the protein SMN. A second gene, SMN2, can also produce SMN, but it is much less efficient than SMN1 at doing so. Developing ways to increase SMN production by SMN2 are therefore of potential therapeutic interest.
In a study that appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Charlotte Sumner and colleagues from the NIH show that in a mouse model of SMA a drug known as trichostatin A (TSA) can increase the amount of SMN2 produced SMN in both neural tissues and muscles (the tissues that are affected in humans with SMA). Importantly, daily administration of TSA (which is a hydroxamic acid HDAC inhibitor) to mice already showing signs of SMA-like disease improved their chances of survival and attenuated their disease symptoms. This study therefore provides support for the idea that hydroxamic acid HDAC inhibitors should be developed for the treatment of individuals with SMA.
TITLE: Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy
AUTHOR CONTACT:
Charlotte J. Sumner
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 435-9288; Fax: (301) 480-3365; E-mail: sumnerc@ninds.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29562
ONCOLOGY: Akt makes melanomas grow downward
Early stage melanomas grow superficially in a radial manner and can be treated by surgery. By contrast, advanced stage melanomas grow vertically, gaining the ability to invade other tissues and metastasize to distant organs, and are usually highly resistant to chemotherapy and radiation. Understanding the molecular differences between radial and vertical growth melanomas might provide new targets for the development of drugs to treat individuals with advanced stage melanoma.
In a study that appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Jack Arbiser and colleagues from Emory University, Atlanta, show that overexpression of Akt in a radial growth human melanoma cell line endows the tumor cells with the ability to grow when transplanted into immunocompromised mice. This ability to grow invasively was associated with increased production of reactive oxygen. This study therefore indicates that overexpression of Akt alone can convert a radial growth melanoma cell line into a highly invasive tumor cell line, leading the authors to suggest that Akt and the pathways that generate reactive oxygen might provide targets for the development of drugs to treat individuals with advanced stage melanoma.
TITLE: Overexpression of Akt converts radial growth melanoma to vertical growth melanoma
AUTHOR CONTACT:
Jack L. Arbiser
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 727-5063; Fax: (404) 727-0923; E-mail: jarbise@emory.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30102
METABOLIC DISEASE: PKC-epsilon links fat to insulin resistance
The accumulation of fat in the liver (hepatic steatosis) can result in non-alcoholic fatty liver disease, which is associated with hepatic insulin resistance and type 2 diabetes mellitus. However, the mechanisms by which fat accumulation leads to hepatic insulin resistance have not been well characterized. Now, researchers from Yale University have shown that a protein known as PKC-epsilon has an important role in the development of fat-induced hepatic insulin resistance in rats
In the study, which appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Gerald Shulman and colleagues show that although specifically decreasing the expression of PKC-epsilon in the liver and white adipose tissue of rats did not decrease fat accumulation following 3 days on a high-fat diet, it did protect the rats from developing hepatic insulin resistance. Further analysis showed that PKC-epsilon interacts with the insulin receptor and inhibits signaling downstream of the insulin receptor, providing a molecular mechanism for the lack of hepatic insulin resistance in the rats expressing low levels of PKC-epsilon in the liver and white adipose tissue. This identification of PKC-epsilon as a mediator of hepatic steatosis–induced hepatic insulin resistance in rats provides a new potential target for the development of therapeutics to treat individuals with non-alcoholic fatty liver disease and type 2 diabetes mellitus.
TITLE: Inhibition of protein kinase C-epsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease
AUTHOR CONTACT:
Gerald I. Shulman
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-5447; Fax: (203) 737-4059; E-mail: gerald.shulman@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30400
IMMUNOLOGY: Neutrophils need glucose-6-phosphatase–beta
Many human diseases, including glycogen storage disease type Ib (GSD-Ib) and Shwachman-Diamond syndrome, are characterized by defects in neutrophil number and/or function. However, the underlying cause(s) of the neutrophil defects is not well understood. Now, researchers from the NIH have identified a new cause of defective neutrophil number and function in mice.
In the study, which appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Janice Chou and colleagues show that mice lacking the protein glucose-6-phosphatase–beta (G6Pase-beta) — which helps cells release glucose into the blood — have decreased numbers of neutrophils and the remaining neutrophils exhibit impaired function. These neutrophil defects made the mice more susceptible to bacterial infection than normal mice. Because the protein content of the endoplasmic reticulum (ER) of cells isolated from bacterially infected mice lacking G6Pase-beta resembled the ER of cells exposed to ER stress, the authors suggest that one mechanism behind the loss of neutrophil numbers in mice lacking G6Pase-beta is ER stress–mediated neutrophil death. Furthermore, they suggest that it “will be of interest to see whether G6Pase-beta mutations are associated with diseases in which intermittent neutropenia or neutrophil dysfunction emerges in the presence of stress or immune challenge”.
TITLE: Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase–beta
AUTHOR CONTACT:
Janice Y. Chou
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-1094; Fax: (301) 402-6035; E-mail: chouja@mail.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30443
IMMUNOLOGY: Unique cell population involved in granuloma formation in the intestine
Infection with some microbes (such as the microbe that causes tuberculosis) and some cases of tissue damage (such as occurs in Crohn disease) result in a localized chronic inflammatory response that causes the formation of granulomas (small cellular nodules). Although the cellular content of granulomas is reasonably well characterized, epitheloid cells (probably immune cells known as macrophages) surrounded by immune cells known as lymphocytes, the mechanisms of granuloma formation are not well defined.
In a study that appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Atsushi Mizoguchi and colleagues from Massachusetts General Hospital, Boston, identify a unique cell population that promotes intestinal granuloma formation in mice. This cell population was defined by expression of the dendritic cell (DC) marker CD11c and the macrophage marker F4/80 and by production of the soluble factor IL-23. These DC-like cells were unable to induce granuloma formation in the presence of IL-4 and IgG and if microbes were absent from the gut, indicating that both host and environmental factors can modulate granuloma formation induced by these cells. This study therefore identifies a population of cells that is crucial for granuloma formation under Th1 conditions. As others have recently identified a similar population of cells in the lungs of mice infected with the agent that causes tuberculosis it seems probable that these cells will have a role in granuloma formation in other tissues.
TITLE: Dependence of intestinal granuloma formation on unique myeloid DC-like cells
AUTHOR CONTACT:
Atsushi Mizoguchi
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-8492; Fax: (617) 643-3566; E-mail: amizoguchi@partners.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30150
ENDOCRINOLOGY: Mice and humans with an MCT8 defect are not completely alike
In several families it has been shown that children with an imbalance in their serum levels of thyroid hormones as well as neurological and mental deficits (psychomotor retardation) have a defect in their MCT8 gene. But why defects in MCT8 — which produces a protein that allows cells to take up thyroid hormones — cause these thyroid hormone defects and psychomotor retardation is not clear, in part, because there are few animal models of the disease. In a study that appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Heike Heuer and colleagues studied mice lacking MCT8 and found that they exhibited similar patterns of thyroid hormone imbalance to humans with an MCT8 gene defect. However, the mice did not develop neurological defects, leading the authors to suggest that mice, but not humans, have thyroid hormone transporters able to compensate for the lack of MCT8. Identifying these transporters is important for the development of a good mouse model of the psychomotor retardation caused by MCT8 gene defects in humans, something that is crucial for increasing our understanding of the human disease.
TITLE: Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8
AUTHOR CONTACT:
Heike Heuer
Leibniz Institute for Age Research/Fritz Lipmann Institute, Jena, Germany.
Phone: +49-3641-656021; Fax: +49-3641-656040; E-mail: hheuer@fli-leibniz.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28253
PHYSIOLOGY: Adenosine teaches the lungs to cope with low levels of oxygen
Hypoxia, which is defined as a shortage of oxygen, can occur throughout the body (e.g., at high altitude) or within a specific organ or tissue of the body (e.g., due to blockage of a blood vessel, which in the heart ultimately results in a heart attack). In many instances, inflammation is the response of the body to hypoxia and this often causes many of the problems that arise from hypoxia. However, the body can be protected from some of the more severe effects of hypoxia by hypoxic preconditioning (HPC), i.e., exposure to moderately decreased amounts of oxygen.
In a study that appears online on February 22 in advance of publication in the March print issue of the Journal of Clinical Investigation, Juan Ibla and colleagues from Children’s Hospital Boston, show that if mice undergo HPC their lungs exhibit an attenuated inflammatory response to severe hypoxia compared with mice that received no HPC. In particular, the expression of genes regulated by the pro-inflammatory regulator NF-kappa-B was decreased. This decrease in NF-kappa-B activation was mediated by adenosine produced by cells exposed to HPC. Further analysis showed that adenosine inactivated a protein (cullin-1) that is required for NF-kappa-B activation by a process known as deneddylation. This study identifies an anti-inflammatory mechanism activated in the lungs by HPC and mediated by adensosine. Future studies will investigate whether the same mechanism protects other tissues from the severe effects of hypoxia.
TITLE: Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation
AUTHOR CONTACT:
Juan C. Ibla
Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 355-7737; Fax: (617) 730-0894; E-mail: juan.ibla@childrens.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30049
Journal
Journal of Clinical Investigation