EDITOR'S PICK: Jetting off without the jet lag
Everyone hates the jet lag — the nighttime insomnia, loss of appetite, decreased alertness, and depressed mood — that accompanies travel to locations in different time zones. The symptoms of jet lag are caused by misalignment of a person's internal body clock (also known as the circadian clock) and external time. Now, Gregor Eichele and colleagues, at the Max Planck Institute for Biophysical Chemistry, Germany, have provided new insight into the molecular mechanisms responsible for resetting the internal circadian system in the mouse. One of their key observations indicates that modulating the speed with which the adrenal gland shifts its rhythmic production of glucocorticoid hormones to the new light/dark cycle (the equivalent of the new time zone when considering human travel) regulates the resetting of the entire internal body clock. The authors suggest that their data point to new potential therapies to overcome jet lag.
In an accompanying commentary, Mary Harrington, at Smith College, Northampton, discusses how these data have implications not only for those who suffer jet lag but also for those who perform rotating shift work, which has been linked to many serious health problems, including breast cancer, stroke, and cardiovascular disease. She also cautions that it will be important to determine whether treatments for jet lag that allow the body clock to shift rapidly are actually better for one's health than the slower adjustments that occur naturally.
TITLE: Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag
AUTHOR CONTACT:
Gregor Eichele
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Phone: 49.551.201.2701; Fax: 49.551.201.2705; E-mail: geichel@gwdg.de.
View this article at: http://www.jci.org/articles/view/41192?key=92d376e71c537c307172
ACCOMPANYING COMMENTARY
TITLE: Location, location, location: important for jet-lagged circadian loops
AUTHOR CONTACT:
Mary Harrington
Smith College, Northampton, Massachusetts, USA.
Phone: 413.585.3925; Fax: 413.585.3786; E-mail: mharring@smith.edu.
View this article at: http://www.jci.org/articles/view/43632?key=c153c8c52f1985893e28
EDITOR'S PICK: Selective estrogen targeting to protect the heart and blood vessels
Diseases of the blood vessels and heart, which are known as cardiovascular diseases, are the most common causes of death in the US. They include heart failure and atherosclerosis (also known as hardening of the arteries), which is a common cause of heart attack and stroke. The hormone estrogen is thought to have cardiovascular protective effects. However, hormone therapy with estrogen alone increases the risk of uterine cancer in women. By dissecting the different pathways by which estrogen signals to cells in mice, a team of researchers, led by Philip Shaul, at the University of Texas Southwestern Medical Center, Dallas, has now determined that it might be possible to selectively harness the cardiovascular benefits of estrogen.
Specifically, the team found that an estrogen-dendrimer conjugate that activated only the subset of estrogen receptors (the proteins to which estrogen binds to mediate its effects) that reside at the cell membrane, and not those in the nucleus, promoted cardiovascular protection in mice and did not stimulate either uterine enlargement or breast cancer xenograft growth. In an accompanying commentary, Michael Mendelsohn and Richard Karas, at Tufts Medical Center, Boston, suggest that, "translation of these findings into clinically relevant therapeutic interventions is a logical next goal." However, they caution that there is a long road ahead to realizing this goal.
TITLE: Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
AUTHOR CONTACT:
Philip W. Shaul
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.2015; Fax: 214.648.2481; E-mail: Philip.shaul@utsouthwestern.edu.
View this article at: http://www.jci.org/articles/view/38291?key=c015821411b383d31bcb
ACCOMPANYING COMMENTARY
TITLE: Rapid progress for non-nuclear estrogen receptor signaling
AUTHOR CONTACT:
Michael E. Mendelsohn
Tufts Medical Center, Boston, Massachusetts, USA.
Phone: 617.636.8776; Fax: 617.636.1444; E-mail: MMendelsohn@tuftsmedicalcenter.org.
Richard H. Karas
Tufts Medical Center, Boston, Massachusetts, USA.
Phone: 617.636.8776; Fax: 617.636.1444; E-mail: RKaras@tuftsmedicalcenter.org.
View this article at: http://www.jci.org/articles/view/43756?key=7a8813a647a56ec32c16
EDITOR'S PICK: Knocked of balance by a defect in the cellular process autophagy
A team of researchers, led by Carlos López-Otín, at Universidad de Oviedo, Spain, has identified in mice an essential role for the cellular process known as autophagy in inner ear development and balance sensing. The team hopes that these data will provide new understanding of human balance disorders, which are of increasing relevance as the elderly population expands, and possibly new therapeutic approaches.
Autophagy is an evolutionarily conserved process by which cells consume unwanted cellular constituents and recycle nutrients. The team generated mice lacking the autophagy protein Atg4b and showed that they exhibited a systemic reduction in autophagy. Surprisingly, the mice also exhibited several behaviors characteristic of inner ear disorders, such as head-tilting, circling behavior, and an inability to swim. Further analysis indicated that these behaviors resulted from defective development of otoconia, organic particles that contain calcium carbonate crystals and proteins and that are essential for balance perception. In an accompanying commentary, Suresh Subramani and Andreas Till, at the University of California at San Diego, La Jolla, note that these data indicate a role for autophagy in functions distinct from degrading cellular constituents.
TITLE: Autophagy is essential for mouse sense of balance
AUTHOR CONTACT:
Carlos López-Otín
Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
Phone: 34.985.104201; Fax: 34.985.103564; E-mail: clo@uniovi.es.
View this article at: http://www.jci.org/articles/view/42601?key=332970168abbfde3584d
ACCOMPANYING COMMENTARY
TITLE: A balancing act for autophagin
AUTHOR CONTACT:
Suresh Subramani
University of California at San Diego, La Jolla, California, USA.
Phone: 858.534.2327; Fax: 858.534.0053; E-mail: ssubramani@ucsd.edu.
View this article at: http://www.jci.org/articles/view/43238?key=9e6a81354693ff001d70
METABOLIC DISEASE: Uncovering how the antidiabetic drug metformin really works
Metformin is the drug of choice for treating individuals with type 2 diabetes. It works primarily by suppressing the production of glucose by the liver. Recent data suggest that metformin suppresses glucose production by the liver by activating the protein AMPK. However, a team of researchers, led by Benoit Viollet and Marc Fortez, at Institut Cochin, Paris, has now found that metformin still suppresses glucose production by the liver in mice lacking AMPK. Further analysis revealed that metformin in fact elicits its antidiabetic effects in the liver by reducing intracellular levels of ATP (a molecular energy source). As noted by Morris Birnbaum and Russell Miller, in an accompanying commentary, these data have clinical implications because AMPK is considered an attractive target for the development of new drugs to treat type 2 diabetes.
TITLE: Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state
AUTHOR CONTACT:
Benoit Viollet
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Phone: 33.1.44.41.24.01; Fax: 33.1.44.41.24.21; E-mail: benoit.viollet@inserm.fr.
Marc Foretz
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Phone: 33.1.44.41.24.01; Fax: 33.1.44.41.24.21; E-mail: marc.foretz@inserm.fr.
View this article at: http://www.jci.org/articles/view/40671?key=790d1656177e1b9918f9
ACCOMPANYING COMMENTARY
TITLE: An energetic tale of AMPK-independent effects of metformin
AUTHOR CONTACT:
Morris J. Birnbaum
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.5001; Fax: 215.573.9138; E-mail: birnbaum@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/43661?key=d8599ea6efbaa05057b7
ONCOLOGY: Overcoming the toxic effects of anticancer radiation therapy
Severe side effects, in particular the destruction of blood cell precursors in the bone marrow, limit the efficacy of radiation therapy for the treatment of cancer. Researchers are therefore seeking to develop ways to protect healthy cells from the toxicity of radiation therapy. A team of researchers, led by Normal Sharpless, at the University of North Carolina School of Medicine, Chapel Hill, has now determined that small molecules that inhibit both CDK4 and CDK6 (proteins involved in regulating cell proliferation) mitigate the effects of radiation therapy on blood cell precursors in mice. Importantly, treating tumor-bearing mice with both a CDK4/6 inhibitor and radiation reduced the toxicity of radiation therapy without compromising its therapeutic effects. The authors and, in an accompanying commentary, Andrei Gudkov and Elena Komarova therefore suggest that CDK4/6 inhibitors might provide a way to improve the efficacy of radiation therapy for the treatment of patients with cancer.
TITLE: Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition
AUTHOR CONTACT:
Norman E. Sharpless
University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Phone: 919.966.1185; Fax: 919.966.8212; E-mail: nes@med.unc.edu.
View this article at: http://www.jci.org/articles/view/41402?key=d38538ef0830c50ee887
ACCOMPANYING COMMENTARY
TITLE: Radioprotection: smart games with death
AUTHOR CONTACT:
Andrei V. Gudkov
Roswell Park Cancer Institute, Buffalo, New York, USA.
Phone: 716.845.3902; Fax: 716.845.3944; E-mail: andrei.gudkov@roswellpark.org.
View this article at: http://www.jci.org/articles/view/43794?key=e68964efe2da8fe54d80
TRANSPLANTATION: Noninvasive imaging of heart transplant rejection in mice
Despite the use of drugs that suppress the immune system, rates of graft rejection are high among recipients of heart transplants. Currently, the onset and progression of graft rejection in heart transplant recipients are monitored by serial biopsy. A noninvasive approach to monitor heart transplant recipients would be of tremendous benefit to physicians and patients. Ralph Weissleder, Matthias Nahrendorf, and colleagues, at Massachusetts General Hospital and Harvard Medical School, Boston, have now brought this a step closer to reality by developing a technique that enabled them to define and validate an imaging signature of heart graft rejection in mice. Specifically, they found that noninvasive imaging for the presence of the protein MPO, which is expressed at high levels in immune cells characterized by high levels of expression of the protein Ly-6C, was a signature of hearts that were rejected. The authors therefore suggest that MPO imaging might provide a noninvasive way to monitor heart transplant recipients and identify those likely to reject their grafts.
TITLE: Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice
AUTHOR CONTACT:
Matthias Nahrendorf
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.643.0500; Fax: 617.643.6133; E-mail: mnahrendorf@mgh.harvard.edu.
Ralph Weissleder
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.643.0500; Fax: 617.643.6133; E-mail: rweissleder@mgh.harvard.edu.
View this article at: http://www.jci.org/articles/view/42304?key=57617399a7587616a739
CARDIOVASCULAR DISEASE: Uncovering the causes of hardening of the arteries
Atherosclerosis, or hardening of the arteries, is a disease of the major arterial blood vessels that is a common cause of heart attack and stroke. It is one of the leading causes of death in developed countries. A team of researchers, led by Pek Yee Lum and Xia Yang, at Rosetta Inpharmatics LLC, Seattle, has now studied gene-disease causality relationships in mice susceptible to atherosclerosis. The team identified in the fat tissue and liver of the mice, 292 genes causal for a specific characteristic of atherosclerosis (aortic arch lesion size) and experimentally validated one of these candidate genes using a knockout mouse model. Of clinical significance, the candidates identified by the team were enriched for genes whose functional DNA variation has been shown previously to be associated with atherosclerosis disease risk in humans. The authors believe that further studies using this approach and the data they generate will provide insights into the mechanisms underlying the development of atherosclerosis, a key to developing new therapeutics and diagnostic biomarkers.
TITLE: Identification and validation of genes affecting aortic lesions in mice
AUTHOR CONTACT:
Pek Yee Lum
Rosetta Inpharmatics LLC, Seattle, Washington 98109, USA.
Phone: 206.667.2118; Fax: 206.667.2062; E-mail: pek.lum@ipierian.com.
Xia Yang
Rosetta Inpharmatics LLC, Seattle, Washington 98109, USA.
Phone: 206.667.2118; Fax: 206.667.2062; E-mail: xia.yang@sagebase.org.
View this article at: http://www.jci.org/articles/view/42742?key=8cd16127110ad46bfcb5
HEPATOLOGY: Scar tissue in the liver: how to block its formation
Cirrhosis of the liver is a condition in which scar tissue (fibrotic tissue) slowly replaces healthy liver tissue due to chronic injury caused by any one of a number of insults, including persistent heavy alcohol consumption and infection with hepatitis B or C viruses. This causes the liver to slowly deteriorate and malfunction. A team of researchers, led by Vijay Shah and Sheng Cao, at the Mayo Clinic, Rochester, has now identified a molecular regulator of a key step in the development of liver fibrosis in rats, leading them to suggest that this molecule could be targeted for therapeutic purposes.
A key step in the development of liver fibrosis is the recruitment of cells known as hepatic stellate cells (HSCs). Their recruitment is dependent on the growth factor PDGF, but the molecular mechanisms that regulate the effects of PDGF have not been determined. The team found that the protein neuropilin-1 was central to the effects of PDGF on rat, mouse, and human HSC recruitment in vitro. Furthermore, blocking neuropilin-1 ameliorated recruitment of HSCs and blocked liver fibrosis in a rat model. The authors believe that these data have therapeutic implications because neuropilin-1 overexpression was observed in cirrhotic liver tissue from humans with disease caused by both hepatitis C virus infection and steatohepatitis.
TITLE: Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells
AUTHOR CONTACT:
Vijay H. Shah
Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507.255.6028; Fax: 507.255.6318; E-mail: shah.vijay@mayo.edu.
Sheng Cao
Mayo Clinic, Rochester, Minnesota, USA.
Phone 507.538.7641; Fax: 507.255.6318; E-mail: cao.sheng@mayo.edu.
View this article at: http://www.jci.org/articles/view/41203?key=905e99d7fccd8ab4f10e
Journal
Journal of Clinical Investigation