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1.
Kingsbury MA Yung YC Peterson SE Westra JW Chun J 《Cellular and molecular life sciences : CMLS》2006,63(22):2626-2641
The brain is remarkable for its complex organization and functions, which have been historically assumed to arise from cells
with identical genomes. However, recent studies have shown that the brain is in fact a complex genetic mosaic of aneuploid
and euploid cells. The precise function of neural aneuploidy and mosaicism are currently being examined on multiple fronts
that include contributions to cellular diversity, cellular signaling and diseases of the central nervous system (CNS). Constitutive
aneuploidy in genetic diseases has proven roles in brain dysfunction, as observed in Down syndrome (trisomy 21) and mosaic
variegated aneuploidy. The existence of aneuploid cells within normal individuals raises the possibility that these cells
might have distinct functions in the normal and diseased brain, the latter contributing to sporadic CNS disorders including
cancer. Here we review what is known about neural aneuploidy, and offer speculations on its role in diseases of the brain.
Received 13 April 2006; received after revision 2 June 2006; accepted 13 July 2006 相似文献
2.
This review describes the structure and function of prolyl endopeptidase (PEP) enzymes and how they are being evaluated as
drug targets and therapeutic agents. The most well studied PEP family has a two-domain structure whose unique seven-blade
β-propeller domain works with the catalytic domain to hydrolyze the peptide bond on the carboxyl side of internal proline
residues of an oligopeptide substrate. Structural and functional studies on this protease family have elucidated the mechanism
for peptide entry between the two domains. Other structurally unrelated PEPs have been identified, but have not been studied
in detail. Human PEP has been evaluated as a pharmacological target for neurological diseases due to its high brain concentration
and ability to cleave neuropeptides in vitro. Recently, microbial PEPs have been studied as potential therapeutics for celiac sprue, an inflammatory disease of the small
intestine triggered by proline-rich gluten.
Received 6 July 2006; received after revision 17 August 2006; accepted 1 November 2006 相似文献
3.
Ramírez CL Cadiñanos J Varela I Freije JM López-Otín C 《Cellular and molecular life sciences : CMLS》2007,64(2):155-170
Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes.
With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic
options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances
have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and
Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin
A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged
as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate
that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering
from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.
Received 28 July 2006; received after revision 5 September 2006; accepted 13 October 2006 相似文献
4.
Albert-Weissenberger C Cazalet C Buchrieser C 《Cellular and molecular life sciences : CMLS》2007,64(4):432-448
The bacterial pathogen Legionella pneumophila is found ubiquitously in fresh water environments where it replicates within protozoan hosts. When inhaled by humans it can
replicate within alveolar macrophages and cause a severe pneumonia, Legionnaires disease. Yet much needs to be learned regarding
the mechanisms that allow Legionella to modulate host functions to its advantage and the regulatory network governing its intracellular life cycle. The establishment
and publication of the complete genome sequences of three clinical L. pneumophila isolates paved the way for major breakthroughs in understanding the biology of L. pneumophila. Based on sequence analysis many new putative virulence factors have been identified foremost among them eukaryotic-like
proteins that may be implicated in many different steps of the Legionella life cycle. This review summarizes what is currently known about regulation of the Legionella life cycle and gives insight in the Legionella-specific features as deduced from genome analysis.
Received 1 September 2006; received after revision 10 October 2006; accepted 22 November 2006 相似文献
5.
Tsuji M 《Cellular and molecular life sciences : CMLS》2006,63(16):1889-1898
Natural killer T (NKT) cells have been shown by a number of studies to play a protective role against cancers, autoimmune
diseases and infectious diseases. Several glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant
species have recently been identified as natural ligands (antigens) for NKT cells. Some of these glycolipid/phospholipid ligands
have now been crystallized in forms bound to CD1d molecules, and the tertiary structure of these complexes has finally been
revealed. This review is intended to list natural NKT cell ligands identified to date, and discuss how their structures relate
to their propensity to bind CD1d molecules and, as a consequence, stimulate NKT cells.
Received 14 February 2006; received after revision 31 March 2006; accepted 15 May 2006 相似文献
6.
CAPA peptides have been isolated from a broad range of insect species as well as an arachnid, and can be grouped into the
periviscerokinin and pyrokinin peptide families. In insects, CAPA peptides are the characteristic and most abundant neuropeptides
in the abdominal neurohemal system. In many species, CAPA peptides exert potent myotropic effects on different muscles such
as the heart. In others, including blood-sucking insects able to transmit serious diseases, CAPA peptides have strong diuretic
or anti-diuretic effects and thus are potentially of medical importance. CAPA peptides undergo cell-type-specific sorting
and packaging, and are the first insect neuropeptides shown to be differentially processed. In this review, we discuss the
current knowledge on the structure, distribution, receptors and physiological actions of the CAPA peptides.
Received 28 April 2006; received after revision 5 June 2006; accepted 4 July 2006 相似文献
7.
M Debray-Sachs R Assan D Bailey J Hamburger 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1978,287(12):1161-1164
It is usually accepted that macrophages "activated" by lymphokines may be found cytotoxic against tumoral target cells but show no detectable cytotoxicity in in vitro tests using normal non tumoral cells as target cells. These data have been obtained mainly with the chromium-release test. The present paper describes a new test using normal isolated pancreatic cells as target cells and evaluating the effect of activated or non-activated macrophages on the insulin secretion response to glucose stimulation. The results show a striking decrease in this response following an 18-hr incubation of pancreatic islet cells with activated macrophages, as compared to that of the same cells incubated with control macrophages. This is clear evidence that activated macrophages may alter normal cells and suggests that their cytotoxic properties are not restricted to tumoral target cells. 相似文献
8.
During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in
neurodegeneration, particularly in pathologies such as Alzheimer’s (AD) and Parkinson’s (PD) disease. Evidence from epidemiological
studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials
with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used
as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative
diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze
the molecular (cyclooxygenases, secretases, NF-κB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial
cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.
Received 4 December 2006; received after revision 24 January 2007; accepted 23 February 2007 相似文献
9.
Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease 总被引:5,自引:0,他引:5
The DSCR1 (Adapt78) gene1 is transiently induced by stresses to temporarily protect cells against further potentially lethal challenges. However, chronic
expression of the DSCR1 (Adapt78) gene has now been implicated in several pathological conditions including Alzheimer’s disease, Down syndrome and cardiac
hypertrophy. Calcipressin 1 has been shown to function through direct binding and inhibition of the serine threonine protein
phosphatase Calcineurin. Pharmacological inhibition of calcineurin, by the immunosuppressive drugs cyclosporin A and FK506,
affects a wide variety of diseases. It is, therefore, likely that this endogenous calcineurin inhibitor, calcipressin 1, may
also play a role in a variety of human diseases.
1Please note that the mammalian DSCR1 gene is also called Adapt78 or RCAN1, and its protein products have been named Calcipressin1, MCIP1 and RCAN1. A proposal to adopt a single gene name of RCAN1 and a protein name RCAN1 (for Regulator of Calcineurin) has been endorsed by the HUGO Gene Nomenclature Committee, but final
approval must await agreement from a majority of researchers in the field.
Received 2 March 2005; received after revision 27 May 2005; accepted 19 July 2005 相似文献
10.
Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease 总被引:1,自引:1,他引:0
Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease
(AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain.
Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with
secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin,
(iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular
environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize
preformed Aβ fibrils.
Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006 相似文献
11.
Hashimoto H 《Cellular and molecular life sciences : CMLS》2006,63(24):2954-2967
Carbohydrate-binding modules (CBMs) are found in many carbohydrate-active enzymes. CBMs bind to a range of polysaccharides,
their primary function being to increase the catalytic efficiency of the carbohydrate-active enzymes against soluble and/or
insoluble substrates. CBMs bind to their target ligands with high specificities and affinities. Thus, CBM systems are excellent
models to study the mechanism of protein-carbohydrate interaction. To date, CBMs have been classified into 45 different families
and many structural and functional studies have been reported. At present, three-dimensional structures of CBMs from 31 different
families have been determined. These structures demonstrate that the fold most commonly found in CBMs is the β-sandwich. In
the past few years, about 10 new structures from different families have been reported. These enable detailed classification
of CBM structures. This article reviews recent structural and functional studies of CBMs and discusses the sub-classification
of β-sandwich CBMs.
Received 28 April 2006; received after revision 12 July 2006; accepted 14 September 2006 相似文献
12.
T. J. Hall 《Cellular and molecular life sciences : CMLS》1994,50(11-12):1048-1053
Interleukin-1 and tumor necrosis factor-alpha are potent, multifunctional cytokine mediators of inflammation and immune responses that are produced primarily by activated monocytes and macrophages. Three published papers by different groups have shown that heat shock and chemical stress with heavy metal salts or sulfhydryl reagents, all of which induce the expression of heat shock protein 70 (hsp70), concomitantly inhibit the production of these cytokines in human monocytes and mouse macrophages activated by lipopolysaccharide. These papers are reviewed and discussed in some detail. Other studies suggest that various anti-inflammatory drugs, including acetylsalicyclic acid, auranofin and dexamethasone, can also facilitate HSP expression in macrophages. However, while these studies are interesting, it is clear that not a great deal of work has been done and/or published in this area. Since many pharmaceutical companies are developing cytokine synthesis inhibitors as potential anti-inflammatory drugs, one aim of this article is to emphasize that understanding the molecular mechanism(s) that lead to increased HSP expression and decreased cytokine biosynthesis may assist in achieving this goal. 相似文献
13.
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought
to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that
result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding:
the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation
of aberrantly folded proteins. Molecular chaperones – such as protein-disulfide isomerase, glucose-regulated protein 78, and
heat shock proteins – can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing
their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here,
we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
Received 5 December 2006; received after revision 7 February 2007; accepted 15 March 2007 相似文献
14.
Antiquitin is a member of the aldehyde dehydrogenase superfamily. Sequence analyses indicate that the protein is highly conserved
from plants to animals. The plant antiquitins are generally believed to play a role in osmoregulation and/or detoxification.
The physiological functions of animal antiquitins remain largely elusive, their involvement in a number of human diseases
has been implicated.
Received 28 February 2006; received after revision 13 July 2006; accepted 31 August 2006 相似文献
15.
Tauopathies are a group of neurodegenerative diseases characterised by intracellular deposits of the microtubule-associated
protein tau. The most typical example of a tauopathy is Alzheimer’s disease. The importance of tau in neuronal dysfunction
and degeneration has been demonstrated by the discovery of dominant mutations in the MAPT gene, encoding tau, in some rare dementias. Recent developments have shed light on the significance of tau phosphorylation
and aggregation in pathogenesis. Furthermore, emerging evidence reveals the central role played by tau pre-mRNA processing
in tauopathies. The present review focuses on the current understanding of tau-dependent pathogenic mechanisms and how realistic
therapies for tauopathies can be developed.
Received 3 December 2006; received after revision 23 February 2007; accepted 20 March 2007 相似文献
16.
Liao HF Yang YC Chen YY Hsu ML Shieh HR Chen YJ 《Cellular and molecular life sciences : CMLS》2007,64(1):104-111
Dendritic cells (DC) are specialized antigen-presenting cells. Bone marrow monocytes have been widely used to generate murine
myeloid DC. We found that mouse macrophages derived from bone marrow CD11b+ monocytes influenced the differentiation of these precursors into DC. Modulation of differentiation was demonstrated by the
down-regulation of CD11c, CD40, and CD86 expression and by IL-12 production. DC differentiated in the presence of conditioned
medium from bone marrow-derived macrophage culture (MCM) had impaired ability to stimulate proliferation of, and IFN- γ production
by, allogeneic CD4+ T cells. This inhibition of DC differentiation was mainly mediated by secretory products from macrophages but not by cell-cell
contact. MCM contained higher concentrations of macrophage-colony-stimulating factor (M-CSF), IL-10, and TGF- β1, whereas
IL-6 remained unchanged compared with conditioned medium from fresh monocytes. M-CSF may be the major mediator in MCM inhibiting
DC differentiation. This study demonstrates an important influence of bone marrow-derived macrophages on DC precursors during
DC differentiation.
Received 12 September 2006; received after revision 20 October 2006; accepted 13 November 2006 相似文献
17.
Complex diseases arise from a combination of heritable and environmental factors. The contribution made by environmental factors
may be mediated through epigenetics. Epigenetics is the study of changes in gene expression that occur without a change in
DNA sequence and are meiotically or mitotically heritable. Such changes in gene expression are achieved through the methylation
of DNA, the post-translational modifications of histone proteins, and RNA-based silencing. Epigenetics has been implicated
in complex diseases such as cancer, schizophrenia, bipolar disorder, autism and systemic lupus erythematosus. The prevalence
and severity of these diseases may be influenced by factors that affect the epigenotype, such as ageing, folate status, in vitro fertilization and our ancestors’ lifestyles. Although our understanding of the role played by epigenetics in complex diseases
remains in its infancy, it has already led to the development of novel diagnostic methods and treatments, which augurs well
for its future health benefits.
Received 6 December 2006; received after revision 29 January 2007; accepted 15 March 2007 相似文献
18.
Insights into autotransplantation: the unexpected discovery of specific induction systems in bone marrow stromal cells 总被引:2,自引:0,他引:2
Dezawa M 《Cellular and molecular life sciences : CMLS》2006,63(23):2764-2772
Many kinds of cells, including embryonic stem cells and tissue stem cells, have been considered candidates for transplantation
therapy for neuro- and muscle-degenerative diseases. Bone marrow stromal cells (MSCs) also have great potential as therapeutic
agents since they are easily isolated and can be expanded from patients without serious ethical or technical problems. Recently,
new methods for the highly efficient and specific induction of functional neurons and skeletal muscle cells have been developed
for MSCs. These induced cells were transplanted into animal models of stroke, Parkinson’s disease and muscle degeneration,
resulting in the successful integration of transplanted cells and improvement in the behavior of the transplanted animals.
Here I describe the discovery of these induction systems and focus on the potential use of MSC-derived cells for ‘auto-cell
transplantation therapy’ in neuro- and muscle-degenerative diseases.
Received 27 April 2006; received after revision 5 June 2006; accepted 22 August 2006 相似文献
19.
Penkowa M Espejo C Ortega-Aznar A Hidalgo J Montalban X Martínez Cáceres EM 《Cellular and molecular life sciences : CMLS》2003,60(6):1258-1266
Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission. 相似文献
20.
Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in
various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how
the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed
these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins,
chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced
by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also
has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture
and of the amino acid homo-sequence on pathology.
Received 3 March 2006; received after revision 19 April 2006; accepted 22 May 2006 相似文献