EDITOR'S PICK: Treatment with SN reduces injury to the brain following stroke
Stroke is the term used to describe deteriorating brain function due to either the leaking of blood vessels (hemorrhage) or oxygen deprivation (ischemia) in the brain. Secretoneurin (SN) is a neural protein with various roles in the normal functioning of the brain and nervous system. For example, SN increases blood vessel formation in mouse corneas, and its production is increased following transient brain ischemia in gerbils. In a new study, a team of researchers from the Academia Sinica, Republic of China, and the China Medical University, Republic of China, have revealed a neuroprotective role for SN in a rat model of stroke.
SN production by rats was found to be increased in brain neuronal and endothelial cells following the induction of ischemia in the brain. In vitro, SN treatment improved the survival of primary brain cell cultures subjected to oxygen/glucose deprivation. Cell rescue was dependent on SN-induced expression of proteins that prevent a form of cell death called apoptosis. Furthermore, when rats with ischemia-induced stroke were injected with SN, they exhibited reduced cerebral tissue death, improved motor performance, and enhanced brain function. In addition, stem cell targeting to the brain and subsequent blood vessel formation were also incited by SN injection in these animals. From these results, the authors suggest that SN holds promise as a powerful small-molecule drug in the treatment of stroke.
TITLE: Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke
AUTHOR CONTACT: Hung Li
Academia Sinica, Nankang, Taipei, Republic of China.
Phone: 886-2-2788-0460; Fax: 886-2-2782-6085; E-mail: firstname.lastname@example.org.
China Medical University and Hospital, Taichung, Taiwan, Republic of China.
Phone: 886-4-2205-2121 ext. 6034; Fax: 886-4-2208-0666; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32723
CARDIOVASCULAR DISEASE: PL(u)C(king) the cells from the plaques: Targeting PLC-beta-3 in the treatment of atherosclerosis
Atherosclerosis is an inflammatory disease of the arterial blood vessels enhanced by the presence of immune cells known as macrophages. Macrophages migrate to the cholesterol-rich atherosclerotic plaques that form in the blood vessels and are the central component of atherosclerotic disease. Phospholipase C (PLC) is a protein that has known importance in immune cell signaling, although no specific known function in atherosclerosis. But now, Dianqing Wu and colleagues from Yale University School of Medicine, New Haven, have discovered that the beta-3 form of PLC plays an important role in encouraging macrophage survival within atherosclerotic plaques.
The authors generated mice deficient in PLC-beta-3. Although macrophages from these mice retained many of their normal functions, they were hypersensitive to inducers of a form of cell death known as apoptosis. Mice deficient in the protein apoE are more susceptible to atherosclerosis than normal mice. In the study, mice deficient in both apoE and PLC-beta-3 proteins were shown to have fewer macrophages within their atherosclerotic plaques, more macrophage apoptosis within the plaques, and smaller atherosclerotic plaques compared to mice deficient in apoE alone. Because only macrophages appeared to be effected by the PLC-beta-3 deficiency, and because the effect on these macrophages seemed to be limited to their sensitivity to apoptosis, the authors concluded that PLC-beta-3 might provide a new therapeutic target in the prevention of atherosclerosis.
TITLE: Phospholipase C beta-3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice
AUTHOR CONTACT: Dianqing Wu
Yale University School of Medicine, New Haven, Connecticut, USA
Phone: (203) 785-3149; Fax: (203) 737-1097; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33139
CARDIOVASCULAR DISEASE:OutRAGEd by atherosclerosis
Atherosclerosis is an inflammatory disease of the arterial blood vessels often referred to as “hardening” or “furring” of the arteries because of the plaques that form in the blood vessels. Rupture of these atherosclerotic plaques is the main cause of heart attacks and strokes. Perturbation of the function of the endothelial cells that line the arteries is a crucial event in the initiation of atherosclerosis. New data generated by Ann Marie Schmidt and colleagues at Columbia University Medical Center, New York, using the apoE–/– mouse model of atherosclerosis has indicated a role for a protein known as RAGE in triggering endothelial cell dysfunction.
In the study, both apoE–/– mice also lacking RAGE and apoE–/– mice engineered to express a dominant negative form of RAGE in endothelial cells developed less severe atherosclerosis than apoE–/– mice. Decreased atherosclerotic disease was associated with a less dramatic loss of endothelial cell function and decreased vascular inflammation. The relevance of these observations to human disease was highlighted by the demonstration that both expression of DN-RAGE and knockdown of RAGE expression in human aortic endothelial cells prevented RAGE ligands inducing endothelial cell dysfunction.
TITLE: Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice
AUTHOR CONTACT: Ann Marie Schmidt
Columbia University Medical Center, New York, New York, USA.
Phone: (212) 305-6406; Fax: (212) 305-5337; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32703
ONCOLOGY: A Neu protein target in the treatment of breast cancers
Overexpression of the protein EphA2 in aggressive breast cancer is common, and generally leads to poor outcome for the patient. However, the function of Eph2A in cancer progression is controversial, with conflicting evidence suggesting both pro- and anti-cancer roles for the protein. In a new study, Jin Chen and colleagues from Vanderbilt University School of Medicine, Nashville, have presented evidence that the role Eph2A in breast cancer is highly context dependent.
EphA2 expression was eliminated in two different mouse models of breast cancer that mimic the progression of human tumors through the various stages. MMTV-Neu is a mouse model for overexpression of NEU, a cancer-causing gene (oncogene) that is overexpressed in about 30% of human breast cancer cases. In contrast, the MMTV–PyV-mT mouse models multistep progression of human breast cancers by activation of a number of oncogenes. The researchers found that EphA2 deficiency in MMTV-Neu mice impaired both the initiation of tumor growth and the progression of metastasis. Further analysis of mouse cells revealed that the presence of EphA2 enhanced tumor growth and movement by binding Neu. In addition, treatment of MMTV-Neu mice with an anti-EphA2 therapy reduced tumor volume. In contrast, EphA2 deletion had no noticeable effect on cancer progression in the MMTV-PyV-mT mice. The authors therefore concluded that EphA2 interacts with Neu to enhance tumor progression, and might be a novel target for treating individuals with tumors dependent on Neu signaling.
TITLE: The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling
AUTHOR CONTACT: Jin Chen
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 343-3819; Fax: (615) 343-8648; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33154
ONCOLOGY: Kidney cancer steps it up a Notch: new role for Notch signaling in clear cell renal cell carcinoma
Clear cell renal cell carcinoma (CCRCC) is a form of kidney cancer that accounts for approximately 75% of all kidney cancers. Although inactivation of the VHL gene has a central role in the development of CCRCC, it has been postulated that other events are also required for tumor formation. New research by Håkan Axelson and colleagues at Lund University, Sweden, has now confirmed this, identifying a role for the Notch signaling cascade in the growth of CCRCC cells in vivo and in vitro.
In the study, the Notch signaling cascade was shown to be constitutively active in human CCRCC cell lines independently of any effects of the VHL protein. Blocking Notch signaling in vitro attenuated the growth of the CCRCC cell lines. Similarly, treating immunocompromised mice with an inhibitor of Notch signaling prevented transplanted human CCRCC cells from growing. The authors therefore suggested that targeting the Notch signaling cascade might provide a new avenue for the development of therapeutics to treat individuals with CCRCC.
TITLE: Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo
AUTHOR CONTACT: Håkan Axelson
Lund University, University Hospital MAS, Malmö, Sweden.
Phone: 46-40337621, Fax: 46-40337063, Email: email@example.com.
MEDIA CONTACT: Johanna Sandahl
Lund University, Malmö, Sweden.
Phone: 46-2223178; Email: Johanna.Sandahl@med.lu.se.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32086
ONCOLOGY: The long and winding TRAIL to cancer
Two new mouse studies to be published in the January issue of the Journal of Clinical Investigation have provided insight into the role of the death-inducing protein TRAIL and its receptors in tumor development and metastasis.
Binding of TRAIL to its receptors induces the cells expressing the receptors to undergo a form of cell death known as apoptosis. Wafik El-Deiry and colleagues from the University of Pennsylvania, Philadelphia, found that if lymphoma-prone mice were deficient in the TRAIL receptor they developed lymphoma more frequently than TRAIL receptor–sufficient lymphoma-prone mice. In addition, the lymphoma was more likely to metastasize. Consistent with these effects in lymphoma-prone mice, normal mice deficient in the TRAIL receptor developed more irradiation-induced lung tumors and more chemical-induced liver tumors than normal TRAIL-sufficient mice. Further analysis showed a role for the TRAIL receptor in controlling chronic inflammation, leading the authors to suggest that the TRAIL receptor functions as a suppressor of inflammation and tumor development in multiple tissues.
Using a multistage model of squamous cell skin cancer, a team of researchers from the German Cancer Research Center, Heidelberg, and the Fred Hutchinson Cancer Research Center, Seattle, found a role for the TRAIL receptor in tumor metastasis but not primary tumor development. TRAIL receptor–deficient mice treated with a chemical on the skin, developed tumors at the same rate, and tumors of the same size, as normal mice. However, the skin tumors in the TRAIL receptor–deficient mice metastasized to the lymph nodes more frequently, leading the authors to suggest that agonists of the human receptors for TRAIL might reduce the incidence of metastasis.
TITLE: TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis
AUTHOR CONTACT: Wafik S. El-Deiry
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-9015; Fax: (215) 573-9139; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29900
TITLE: TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development
AUTHOR CONTACT: Henning Walczak
Imperial College London, London, United Kingdom.
Phone: 49-6221-423700; Fax: 49-6221-423799; E-mail: email@example.com.
Christopher J. Kemp
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: (206) 667-4252; Fax: (206) 667-5815; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33061
CARDIOLOGY: Stressed-out hearts put MEF2D to work
Injury to the human heart, such as caused by high blood pressure and heart attack, results in the enlargement of heart muscle cells (cardiomyocyte hypertrophy) and the activation of a fetal program of cardiac gene expression. This pathological response leads to heart failure and death. On a molecular level, this pathological response is driven by enhanced expression of genes in response to the presence of proteins named transcription factors, including the MEF2 family of transcription factors. However, whether the MEF2 transcription factors are required for heart disease to occur had not been determined. A new study by Eric Olsen and his colleagues at the University of Texas Southwestern Medical Center, Dallas, has now revealed a unique role for MEF2D in regulating the pathological cardiac response to stress in adult mouse hearts.
The researchers generated mice deficient in MEF2D, and found that hearts from these mice exhibited blunted responses to cardiac stress. In particular, pressure overload in the hearts of these mice resulted in reduced cardiomyocyte hypertrophy, fetal gene activation, and scarring compared with normal mice. Similar results were seen when cardiac stress was induced with injection of a drug known to cause these conditions. In contrast, overproduction of MEF2D in mice resulted in profound heart disease, evidenced by extensive scarring of the heart tissue, heart dilation, pathological blood clotting, and severely congested lungs and liver. Because MEF2 transcription factors are found in almost all the tissues in the body, the authors concluded from these data that in addition to affecting stress-induced remodeling of the heart, altering MEF2 protein expression might also be a useful therapy for various noncardiac diseases.
TITLE: The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice
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=33255
TRANSPLANTATION: How an antibody makes the CD4+ T cell immune response more aggressive
It is generally believed that signals emanating from the protein Tim-1 on the surface of immune cells known as CD4+ T cells help stimulate the activation of these cells. Consistent with this, Terry Strom and colleagues at the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, have shown that an agonist antibody specific for Tim-1 intensifies the destructive immune response mounted by mouse CD4+ T cells toward nongenetically identical cells. Detailed analysis of the mechanisms behind the enhanced destructive immune response indicated that the agonist Tim-1–specific antibody enhanced the expansion and survival of pro-inflammatory Th1 and Th17 CD4+ T cells and hampered the development of immunosuppressive CD4+ Tregs, as well as deprogramming pre-existing immunosuppressive CD4+ Tregs. These effects meant that when administered to mice, the agonist Tim-1–specific antibody prevented an immunomodulatory drug from blocking the rejection of nongenetically identical pancreatic islet transplants.
TITLE: Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice
AUTHOR CONTACT: Terry B. Strom
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-0850; Fax: (617) 667-0923; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32562
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