Drug that lowers blood pressure might help prevent Alzheimer disease
Alzheimer disease (AD), a neurodegenerative disease that is the most common form of dementia, is characterized by the formation in the brain of plaques containing misfolded beta-amyloid protein. Recent evidence indicates that some drugs used to treat high blood pressure (antihypertensive medications) might reduce the risk of developing AD. In a new study, in which they screened 55 antihypertensive medications in vitro for potential AD-modifying activity, Giulio Maria Pasinetti and colleagues at Mount Sinai School of Medicine, New York, have identified one antihypertensive medication with the ability to reduce AD-like disease in mice.
Only 7 of the 55 antihypertensive medications screened were able to reduce AD-like accumulation of beta-amyloid protein in cultured neurons isolated from mice engineered to be susceptible to an AD-like disease (Tg2576 mice). Of these 7, only 1 (valsartan) was able to markedly reduce the oligomerization of beta-amyloid protein, a feature of memory deterioration. As treatment of Tg2576 mice with valsartan, both before and after the onset of AD-like disease, reduced the severity of disease, the authors suggested that treatment with certain antihypertensive agents might be of benefit to individuals with, or at high risk of developing, AD.
TITLE: Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
AUTHOR CONTACT:
Giulio Maria Pasinetti
Mount Sinai School of Medicine, New York, New York, USA.
Being big hearted isn't always good news
Thickening of the wall of the heart (a process known as cardiac hypertrophy) leads to heart failure and is a major cause of death. There are currently no drugs able to reverse cardiac hypertrophy, in part because our understanding of the molecular mechanisms by which cardiac hypertrophy can be reversed is limited. But now, new research in mice by Cam Patterson and colleagues at the University of North Carolina, Chapel Hill, has identified a mechanism by which the protein atrogin-1 disrupts pathways that promote cardiac hypertrophy.
In the study, atrogin-1 was shown to antagonize Akt-mediated cardiac hypertrophy. Atrogin-1 was found not to inhibit the function of Akt directly but to work by enhancing the activity of proteins known as Forkhead proteins, which repress Akt-dependent cardiac hypertrophy. Further analysis revealed that, at the molecular level, atrogin-1 enhances the activity of Forkhead proteins by inducing their ubiquitylation -- a process whereby the function of a protein is modified by being tagged with a very small, protein known as ubiquitin -- at a specific amino acid, lysine 63.
TITLE: Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
AUTHOR CONTACT:
Cam Patterson
University of North Carolina, Chapel Hill, North Carolina, USA.
Hui-Hua Li,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Histamine receptor makes T cells attack
Mice lacking the histamine H1 receptor (H1R) are less susceptible than normal mice to both experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) and experimental autoimmune orchitis (EAO; a mouse model of orchitis -- autoimmune inflammation of the testicles). New data generated by Corey Teuscher and colleagues at Vermont University, Burlington, has now identified the mechanism underlying this susceptibility.
In the study, CD4+ T cells from mice lacking H1R were found to produce less of the soluble factor IFN-gamma than normal CD4+ T cells when stimulated through their antigen-specific receptor. Reduced IFN-gamma production was associated with impaired activation of the signaling molecule p38 MAPK. However, if H1R expression was restored in H1R-deficient mice in only CD4+ T cells, the CD4+ T cells produced as much IFN-gamma as normal CD4+ T cells and the mice were as susceptible to EAE as normal mice. These data are consistent with a role for H1R in the development of disease-causing, IFN-gamma-producing CD4+ T cells and led the authors to suggest that targeting H1R might be a new approach to treating individuals with autoimmune inflammatory diseases such as multiple sclerosis.
TITLE: Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-gamma production in mice
AUTHOR CONTACT:
Cory Teuscher
University of Vermont, Burlington, Vermont, USA.
Early bird: TGF-beta acts early in a multiple sclerosis-like disease in mice
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS; which comprises the brain and spinal cord). It is characterized by the progressive loss of nerves due to attack by cells of the immune system, which leads to disability. In a new study, Tony Wyss-Coray and colleagues at Stanford University have provided evidence that the soluble factor TGF-beta acts in the CNS in the early stage of disease in a mouse model of MS known as experimental autoimmune encephalomyelitis (EAE). The authors therefore suggest that inhibiting TGF-beta in the early stages of disease might provide benefit to individuals with CNS inflammatory disorders such as MS.
Expression of TGF-beta and TGF-beta-induced signaling were detected in the CNS several days before the onset of paralysis in mice. Consistent with a central role for TGF-beta in initiating disease, intraperitoneal administration of an inhibitor of TGF-beta signaling ameliorated disease and reduced the accumulation in the CNS of immune cells able to attack the nerves. As further analysis indicated that the inhibitor of TGF-beta signaling mediated its effects in the CNS, the authors concluded that " early production of TGF-beta in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation".
TITLE: Glia-dependent TGF-beta signaling, acting independent of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis
AUTHOR CONTACT:
Tony Wyss-Coray
Stanford University School of Medicine, Stanford, California, USA.
TGF-beta gets in the way in the lungs
The fourth-leading cause of death in the world is chronic obstructive pulmonary disease (COPD), which is often a result of smoking. One of the main causes of airway obstruction in individuals with COPD is thickening of the airway walls. Previous studies have suggested that squamous metaplasia (SM; the reversible replacement of the normal columnar airway epithelial cells by squamous epithelial cells) might be one mechanism by which the airway walls thicken in individuals with COPD. Support for this hypothesis has now been provided in a new in vitro study of human lung tissue by Stephen Nishimura and colleagues at the University of California at San Francisco.
In addition to correlating SM with increased severity of COPD, the authors identified some of the mediators that link SM to airway-wall thickening -- IL-1-beta and TGF-beta. Increased secretion of IL-1-beta by airway epithelial cells undergoing SM was found to induce fibroblasts in the walls of the airways to mediate a fibrotic response, including the production of TGF-beta, which then amplified SM. These data suggest that targeting TGF-beta might provide a new approach to treating individuals with COPD.
TITLE: Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients
AUTHOR CONTACT:
Stephen L. Nishimura
University of California at San Francisco, San Francisco, California, USA.
Who's the BOS? The cells mediating chronic lung rejection
Although immunosuppressive drugs prevent a transplanted organ being rejected in the short term, they are unable to prevent chronic transplant rejection (the long term loss of function of a transplanted organ as a result of fibrosis of the internal blood vessels of the transplant). In lung transplantation, bronchiolitis obliterans syndrome (BOS) is the cause of chronic rejection and is the most common reason for lung transplants failing. New insight into the cellular mechanisms of BOS has now been provided by William Burlingham and colleagues at the University of Wisconsin, Madison, who studied the immune responsiveness of peripheral blood cells from recipients of a lung transplant over a 7-year period.
In the study, peripheral blood cells isolated from patients who had received a lung transplant were found to respond to a protein known as collagen type V [col(V)], whereas peripheral blood cells isolated from healthy individuals did not. Strong col(V) responses were associated with increased incidence and severity of BOS and were mediated by immune cells known as CD4+ T cells and the soluble factors IL-17, TNF-alpha, and IL-1-beta. The authors therefore concluded that col(V)-reactive CD4+ T cells producing IL-17 and monocyte/macrophage accessory cells producing TNF-alpha and IL-1-beta facilitate the onset of BOS.
TITLE: IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants
AUTHOR CONTACT:
William J. Burlingham
University of Wisconsin, Madison, Wisconsin, USA.
Stim1 stops the bleeding
New data generated by Bernhard Nieswandt and colleagues from the University of Wuerzburg, Germany, has identified the protein Stim1 as a crucial regulator of the function of platelets, the anucleated cells that are key to stopping bleeding.
Changes in the amount of calcium (Ca2+) in the body of a cell control some signaling pathways in nearly all cells. Recently, Stim1 was identified as a sensor of Ca2+ levels in immune cells known as T cells. When activated, Stim1 triggers the release of more Ca2+ into the body of the T cell from intracellular stores. In the new study, mice expressing a constitutively active mutant form of Stim1 were found to have reduced numbers of platelets and an associated bleeding disorder (increased length of time before bleeding stopped). These symptoms were associated with increased basal concentrations of Ca2+ in the body of platelets, which caused them to be in a preactivated state, and an inability to be activated by collagen, a common activator of platelets during bleeding.
TITLE: An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice
AUTHOR CONTACT:
Bernhard Nieswandt
University of W??rzburg, W??rzburg, Germany.
TNF-alpha selects cancerous cells in a mouse model of Fanconi anemia
Individuals with the inherited disease Fanconi anemia (FA) have an increased risk of suffering from cancer, in particular acute myelogenous leukemia (AML). New data generated by a team of researchers from Cincinnati Children's Hospital Medical Center, Cincinnati, and Oregon Health Sciences University, Portland, have indicated that the soluble factor TNF-alpha can facilitate the outgrowth of leukemic cells from hematopoietic stem cells (HSCs) isolated from a mouse model of FA.
Individuals suffer from FA if they inherit two mutated copies of any one of 13 genes, one of which is FANCC. HSCs isolated from mice lacking FANCC were initially inhibited from growing when exposed to TNF-alpha in vitro. However, long-term exposure to TNF-alpha promoted the outgrowth of genetically unstable cells that caused AML when transplanted into mice. These data indicate that exposure to TNF-alpha provides an environment that promotes the selection and growth of preleukemic stem cells in vitro.
TITLE: TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells
AUTHOR CONTACT:
Qishen Pang
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Grover C. Bagby
Oregon Health Sciences University, Portland, Oregon, USA.
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