Rolipram –a potential new treatment for Alzheimer disease
Alzheimer disease (AD) is the most common form of dementia in the elderly and classic clinical features include memory loss, deterioration in speech, and behavioral disturbances. Doctors increasingly concede that central to the cause of AD is the production and accumulation of beta-amyloid (Abeta), which is toxic in the brain. There are only a few clinical therapeutic options for AD patients but in the December 1 issue of the Journal of Clinical Investigation, Ottavio Arancio, Michael Shelanksi, and colleagues from Columbia University, New York, propose a new treatment to counter AD-associated memory loss.
The authors show that brief treatment of a mouse model of AD with a phosphodiesterase 4 inhibitor, rolipram, improves memory in both long-term potential and contextual learning – both measurements of brain function.
Rolipram's protective effect is due to its ability to modify gene expression, making brain synapses more resistant to the insult caused by the accumulation of Abeta. The beneficial effect of rolipram treatment was found to extend for at least 2 months after the end of one course of the treatment. The authors also found that the beneficial effects of treatment were not limited to early stages of the disease when behavioral changes were initially noted and were actually greater in older mice, suggesting that this class of drug might not be limited to treatment in the initial phases of disease.
Further studies will determine how long improvements in cognitive function persist after a single course of treatment and whether better or more long-lasting results can be achieved with either continuous treatment or successive courses of treatment. This study suggests that drugs, such as rolipram, the inhibit phosphodiesterase have the potential to prevent the memory loss characteristic of Alzheimer disease.
TITLE: Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Ottavio Arancio or Michael Shelanski
Department of Pathology
New York, New York, USA
Phone: 212-342-5527 or 212-305-3300
Fax: 212-342-5524 or 212-305-5498,br> E-mail: email@example.com or firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/press/22831.pdf
New drug protects against the hardening of arteries
Atherosclerosis, a leading cause of morbidity and mortality in Western nations, is caused by the accumulation of cholesterol-rich lipoproteins that adhere to vessel walls and develop into macrophages. These macrophages, laden with lipid, cause inflammation in the vessel and, over time, formation of a lesion. A family of proteins known as PPARs (PPARalpha, PPARbeta, and PPARgamma) are expressed by cells of the artery wall and drugs that activate PPARalpha and PPARgamma (known as PPAR agonists) are used to treat high lipid levels (such as cholesterol and triglycerides), and type 2 diabetes, respectively. The presence of PPARs in the vessel wall has prompted researchers to investigate the effects of PPAR agonists on atherosclerosis in mice. While studies have shown that PPARgamma agonists are beneficial in the treatment of atherosclerosis in mice, the role of other members of this protein family have remained unclear.
In the December 1 issue of the Journal of Clinical Investigation, Andrew Li and colleagues from the University of California, San Diego compare the effects of PPARalpha, PPARbeta, and PPARgamma agonists on the development of atherosclerosis in a mouse model of this disease. They observed profound protective effects of the PPARalpha agonist GW7647, comparable to the PPARgamma agonist rosiglitazone that is currently used to treat type 2 diabetes. GW7647 also reduced weight gain, and insulin and lipoprotein levels. In contrast, lesion development was not inhibited by a PPARbeta agonist.
In an accompanying commentary, Peter Tontonoz and Antonio Castrillo from the University of California, Los Angeles discuss the mechanism described by Li and colleagues by which lipid accumulation is reduced by these agonists, thereby giving us a greater understanding of the roles of PPAR family members in atherosclerosis. Most importantly, the study highlights that the use of a drug (or drugs) that target multiple PPARs, particularly PPARalpha and PPARgamma, may be effective in limiting the accumulation of lipid in macrophages and subsequently reversing atherosclerosis.
TITLE: Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma.
Andrew C. Li or Christopher K. Glass
Department of Cellular and Molecular Medicine
University of California, San Diego, USA
Phone: 858-534-0575 or 858-524-0611
Fax: 858-822-2127 or 858-822-2127
E-mail: email@example.com or firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/press/18730.pdf
TITLE: PPARs in atherosclerosis: the clot thickens
Howard Hughes Medical Institute
UCLA, Los Angeles, California, USA
View the PDF of this commentary at: https://www.the-jci.org/press/23705.pdf
Stem cells to the rescue – or not?
The use of stem cells obtained from bone marrow for the treatment of some skeletal or heart diseases is an attractive long-term strategy to deliver normal stem cells, capable of developing into any cell type of the body, to injured tissue in order to effect repair. A subset of bone marrow cells, called bone marrow–derived side population (BM-SP) cells, make up only 0.01-0.05% of whole bone marrow. In mice, these cells have previously been reported to restore expression of the protein that is lacking in muscular dystrophy. Many studies have shown that stem cells are able to home to injured skeletal and cardiac muscle, however in the past, marker proteins that show the location of donor stem cells within damaged tissue of the recipient have not been able to definitively distinguish between donor and recipient cells, which raises the possibility that the recipients own cells have in fact been responsible for observed regeneration.
In the December 1 issue of the Journal of Clinical Investigation, Elizabeth McNally and colleagues from the University of Chicago transplanted BM-SP cells from normal male mice into female mice lacking delta-sarcoglycan – an animal model of cardiomyopathy and muscular dystrophy – to determine whether these stem cells would be recruited to skeletal and cardiac muscle to restore delta -sarcoglycan expression. Surprisingly, upon examination of many thousands of muscle cells, the authors found that while donor cells readily engrafted into the delta -sarcoglycan–deficient cardiac and skeletal muscle (evidenced by the Y chromosome from male donor cells present within the recipient female muscle), these donor cells were only able to restore sarcoglycan expression in 2 muscle fibers. This finding demonstrates that BM-SP stem cells can produce delta -sarcoglycan but do so at a negligible degree, suggesting that they have a limited potential for cardiac and skeletal muscle regeneration.
In an accompanying commentary, Giulio Cossu, from the Stem Cell Research Institute in Milan discusses how this study "raises additional concerns relating to stem cell plasticity and stem cell therapy in an already heated and controversial field." This study stands in contrast to others that have claimed successful differentiation of BM-SP stem cells in specific tissues. Dr. Cossu offers some reasons for the experimental discrepancies and stresses that "it would be important to repeat the same experiments described here….with other types of stem cells…[as] they may represent a better perspective for the stem cell therapy of striated muscle diseases than BM-SP stem cells." In light of these data, McNally and colleagues suggest that "active pursuit of…alternative approaches should be fully investigated as we advance into regenerative medicine."
TITLE: Transplanted hematopoietic stem cells demonstrate impaired sarcoglycan expression after engraftment into cardiac and skeletal muscle
Department of Medicine
University of Chicago, Chicago, Illinois, USA
View the PDF of this article at: https://www.the-jci.org/press/23071.pdf
TITLE: Fusion of bone marrow–derived stem cells with striated muscle may not be sufficient to activate muscle genes
Stem Cell Research Institute, DIBIT, Milan, Italy
View the PDF of this commentary at: https://www.the-jci.org/press/23733.pdf
Understanding how prostaglandin prevents gut injury during radiation therapy
People undergoing radiation therapy for diseases such as cancer run the risk of irreversibly damaging the cells of their intestine due to the radiation-induced death of cells within the gut. Previous studies have demonstrated that treatment of mice with protaglandin E2 (PGE2) is capable of inhibiting cell death in the intestine that occurs as a result of exposure to radiation.
In the December 1 issue of the Journal of Clinical Investigation, Teresa Tessner and colleagues from the Washington University School of Medicine pursued the mechanism by which PGE2 protects against radiation-induced injury in mice. They demonstrate that radiation-induced cell death can be dependent or independent of the bax protein, however the beneficial effect of PGE2 treatment is only achieved via a bax-dependent mechanism. Bax is normally expressed in the cell cytoplasm, however in response to radiation exposure, bax relocates to the mitochondrial membrane and trigger cell signaling events that lead to cell death. Administration of PGE2 to radiation-exposed mice was found to activate AKT phosphorylation events that block the relocation of bax within the cell, and therefore prevent cell death.
The data suggest that PGE2 or other drugs that increase AKP phosphorylation should reduce injury to the small intestine during radiation therapy. Conversely, cancers with mutations that inactivate bax and block its relocation to the mitochondria may be resistant to radiation therapy. This work may have significant clinical impact if the use of PGE2 could be shown to be effective for protection against radiation-induced gut injury in humans.
TITLE: Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation
Teresa G. Tessner
Washington University School of Medicine
St. Louis, Missouri, USA
View the PDF of this article at: https://www.the-jci.org/press/22218.pdf
Gene therapy rescues the failing heart
Heart failure remains a leading cause of death and researchers continue to search for therapies targeted to the genetic defects causing chronic dysfunction of the heart. Evidence suggests that abnormal transfer of calcium in and out of cardiac cells is key to the inability of the heart to expand and contract correctly. In the December 1 issue of the Journal of Clinical Investigation, Patrick Most and colleagues from Thomas Jefferson University used gene therapy to deliver a calcium-binding protein, S100A1, to rat hearts after they had experienced an infarct. S100A1 levels have been shown to decrease as a result of heart failure in both animals and humans. The authors found that this gene therapy approach restored the levels of S100A1 in the failing heart and returned heart function to normal. The study suggests that further study of this technique may, in the future, translate these findings into clinical trials of S100A1 gene therapy for the treatment of human heart failure.
TITLE: Cardiac adenoviral S100A1 gene delivery rescues failing myocardium
AUTHOR CONTACT: Patrick Most or Walter J. Koch
Center for Translational Medicine
Thomas Jefferson University
Philadelphia, Pennsylvania, USA
E-mail: email@example.com or firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/press/21454.pdf
Investigating the role of T cells in rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory disease leading to joint destruction. Considered by some to be an autoimmune disorder where immune complexes are formed in the joints and excite an inflammatory response, various genetic, environmental, and infectious agents have been suggested as causes of the disease. IL-1 is a proinflammatory molecule produced by cells of the immune system and cells lining the joints and it has been suggested that IL-1 may have a role in the development of RA. The body also produces a natural inhibitor to IL-1, IL-1 receptor antagonist (IL-1Ra), the levels of which are augmented in patients with autoimmune and inflammatory diseases. Another proinflammatory agent, TNF-a, stimulates IL-1 expression and vice versa.
In the December 1 issue of the Journal of Clinical Investigation, Yoichiro Iwakura and colleagues from the University of Tokyo studied the role of T cells in the development of autoimmune arthritis in mice lacking IL-1Ra. The authors demonstrated that mice deficient in both T cells and IL-1Ra did not develop arthritis. Arthritis development also appeared to be markedly decreased in cases of TNF-alpha deficiency. The authors found that IL-1Ra produced by these T cells act on the T cells themselves to induce TNF-alpha expression and TNF-alpha in turn induces OX40 expression on T cells. As inhibition of TNF-a or OX40, the latter being an activation antigen on T cells, which invade tissues and cause autoimmune destruction – was effective in suppressing the development of arthritis, the authors suggest that their study may provide a clue for the development of new therapies for RA.
TITLE: TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice
Center for Experimental Medicine
University of Tokyo
View the PDF of this article at: https://www.the-jci.org/press/20742.pdf
A new concept in immunology: natural killer cells present foreign antigens to T cells
Upon invasion of a tissue by a foreign pathogen or tumor cell, the cellular immune response is put into action: cells known as antigen-presenting cells (APCs) capture and internalize foreign material processing it into smaller peptide fragments, that are then presented on the cell surface to activate naïve T cells to kill the pathogen.
Natural killer (NK) cells are among the first cells of the immune response that arrive at the site of infection or inflammation and their major function is to kill their target cells. In the December 1 issue of the Journal of Clinical Investigation, Ofer Mandelboim, and colleagues from Hebrew University present evidence of a new concept in immunology: the possibility that NK cells actually present antigens from the cells that they kill. This observation offers new and unexpected insight into the direct interaction between NK cells and T cells and suggests an APC-like activating function for human NK cells.
TITLE: Novel APC-like properties of human NK cells directly regulate T cell activation
The Lautenberg Center for General and Tumor Immunology
View the PDF of this article at: https://www.the-jci.org/press/22787.pdf
Halting cell death heals muscular dystrophy
The most common form of muscular dystrophy present at birth is caused by mutation of the LAMA2 gene that encodes laminin-alpha2. Loss of laminin-alpha2 function leads to neuromuscular dysfunction and often early death. Researchers have previously proposed that programmed cell suicide, known as apoptosis, in skeletal muscles and nerves at inappropriate times may be one way in which laminin-alpha2 loss results in muscular dystrophy.
In the December 1 issue of the Journal of Clinical Investigation, Jeffrey Boone Miller and colleagues from Boston Biomedical Research Institute investigated whether the symptoms of muscular dystrophy in laminin-alpha2–deficient mice could be relieved by inhibiting apoptosis in muscle via 2 mechanisms: (i) inactivation of the proapoptotic protein Bax, or (ii) overexpression of the antiapoptosis protein Bcl-2. The authors found that both interventions significantly increased the lifespan of these mice and improved neuromuscular dysfunction. The authors suggest that antiapoptosis therapy may be a possible way in which to relieve neuromuscular dysfunction due to laminin-alpha2 deficiency in humans with muscular dystrophy.
TITLE: Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy
Jeffrey Boone Miller
Boston Biomedical Research Institute
Watertown, Massachusetts, USA
View the PDF of this article at: https://www.the-jci.org/press/22928.pdf
TYK-tock goes the lymphoid tumor clock
The cell signaling pathway known as the JAK-STAT pathway regulates cell growth and survival, and aberrations in this pathway have been shown to exist in multiple solid tumors and leukemia. In the December 1 issue of the Journal of Clinical investigation, Veronika Sexl and colleagues from the Medical University of Vienna describe a role for one of the proteins in this pathway – called TYK2 – in the development of B lymphoid tumors. They show that mice lacking TYK2 developed leukemia with a higher incidence that normal mice. The authors demonstrated that this was due to a decreased ability of natural killer cells and natural killer T cells – which normally attack and destroy foreign, infected or cancerous cells – to act against tumor-derived cells. This data indicates that NK cells are key players in tumor surveillance in such malignancies.
The authors suggest that people deficient in TYK2 may be predisposed to the formation of tumors. In addition, the absence of TYK2 in patients would predict a reduced response to type I interferons, drugs that are currently used to treat chronic myeloid leukemia. Therefore TYK2 deficiency may be relevant to the prognosis of patients as well as to their proper treatment and these patients may consequently have to be treated by alternative means.
TITLE: TYK2 is a key regulator of the surveillance of B lymphoid tumors
Department of Pharmacology
Medical University of Vienna
View the PDF of this article at: https://www.the-jci.org/press/22315.pdf
Copycat bacterial proteins turn the host immune response on itself in Guillain-Barré syndrome
Guillain Barré syndrome (GBS) is a rare disorder in which the body's immune system attacks part of the peripheral nervous system (an autoimmune response) causing weakness and tingling in the extremities that can spread to the entire body causing muscle paralysis that can be life-threatening. GB usually occurs a few days or weeks after the patient has had symptoms of respiratory or gastrointestinal viral infection. The most frequently identified triggering agent of GBS is the bacterium Campylobacter jejuni – the leading cause of bacterial gastroenteritis worldwide.
The presence of bacterial antigens that mimic structures in human tissues has been suggested as a possible mechanism for triggering an autoimmune response after an infection. Researchers have previously suggested that Campylobacter jejuni lipo-oligosaccharides (LOS) may mimic such gangliosides present in human nervous tissue to induce cross-reactve antibodies that lead to GBS. To determine whether specific bacterial genes are crucial for the biosynthesis of ganglioside-like structures and the induction of anti-ganglioside antibodies, Peggy Godschalk and colleagues from Erasmus Medical Center, Rotterdam, characterized the gene locus encoding genes known to be involved in LOS biosynthesis in Campylobacter jejuni strains associated and not associated with GBS.
In the December 1 issue of the Journal of Clinical Investigation, Godschalk and colleagues demonstrate that specific types of the LOS biosynthesis gene locus are associated with GBS and the expression of structures that mimic gangliosides in host tissue. The authors went on to create mutants of 2 of these GBS marker genes, which produced short LOS structures and showed reduced reactivity with GBS patient serum and failed to cause an anti-ganglioside antibody response in mice. The report demonstrates that specific Campylobacter jejuni genes are crucial for the induction of anti-ganglioside antibodies. This increased insight into the biosynthesis of ganglioside mimicking structures may ultimately lead to the development of new treatment strategies and interventions for the treatment of GBS.
TITLE: The crucial role of Campylobacter jejuni genes in anti-ganglioside antibody induction in Guillain Barré syndrome
Peggy C.R. Godschalk
Department of Medical Microbiology and Infectious Diseases
Erasmus MC, Rotterdam, The Netherlands
View the PDF of this article at: https://www.the-jci.org/press/15707.pdf
GLUT4 is at the center of a newly found mechanism of triglyceride production and utilization in type 2 diabetes
TITLE: GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization
Barbara B. Kahn
Beth Israel Deaconess Medical Center
Boston, Massachusetts, USA
View the PDF of this article at: https://www.the-jci.org/press/21341.pdf
TITLE: Metabolic fuel election: the importance of being flexible
Perry E. Bickel
Washington University School of Medicine
St. Louis, Missouri, USA
View the PDF of this commentary at: https://www.the-jci.org/press/23745.pdf
Lack of fibrillin-1 may lead to faulty heart valves
TITLE: TGF-beta–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome
Daniel P. Judge
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA
View the PDF of this article at: https://www.the-jci.org/press/22715.pdf
TITLE: Marfan syndrome and mitral valve prolapse
Arthur E. Weyman
Department of Medicine
Massachusetts General Hospital
Boston, Massachusetts, USA
View the PDF of this commentary at: https://www.the-jci.org/press/23701.pdf
Finding NEMO mutations that impair B cell maturation
TITLE: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland, USA
View the PDF of this article at: https://www.the-jci.org/press/21345.pdf
A new set of T cells found to regulate B cell responses
TITLE: Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell–driven B cell responses
Purdue University, West Lafayette, Indiana, USA.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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