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1.
Dopaminergic neurons in the mammalian brain have received substantial attention in the past given their fundamental role in
several body functions and behaviours. The largest dopaminergic population is found in two nuclei of the ventral midbrain.
Cells of the substantia nigra pars compacta are involved in the control of voluntary movements and postural reflexes, and
their degeneration in the adult brain leads to Parkinson’s disease. Cells of the ventral tegmental area modulate rewarding
and cognitive behaviours, and their dysfunction is involved in the pathogenesis of addictive disorders and schizophrenia.
Because of their clinical relevance, the embryonic development and maintenance of the midbrain dopaminergic cell groups in
the adult have been intensively studied in recent years. In the present review, we provide an overview of the mechanisms and
factors involved in the development of dopaminergic neurons in the mammalian brain, with a special emphasis on the midbrain
dopaminergic population.
Received 17 August 2005; received after revision 28 September 2005; accepted 21 October 2005 相似文献
2.
Hedgehog signaling in pancreas development and disease 总被引:6,自引:0,他引:6
Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during
diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is
not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling
has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation
of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a
variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of
Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic
cancer.
Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005 相似文献
3.
Reddy SV 《Cellular and molecular life sciences : CMLS》2006,63(4):391-398
Paget’s disease of bone is a chronic focal skeletal disorder characterized by increased bone resorption by the osteoclasts.
Paramyxoviral gene products have been detected in pagetic osteoclasts. Paget’s disease is an autosomal dominant trait with
genetic heterogeneity. Several mutations in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) have been
identified in patients with Paget’s disease. Similarly, mutations in the valosin-containing protein (VCP) gene have been shown
to cause inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia. In addition, gene polymorphisms
and enhanced levels of cytokine/growth factors associated with Paget’s disease have been identified. However, the etiologic
factors in Paget’s disease remain elusive. A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62
gene mutations responsible for pagetic osteoclast development and disease severity are unclear. This article will highlight
the etiologic factors involved in the pathogenesis of Paget’s disease.
Received 6 October 2005; received after revision 2 November 2005; accepted 24 November 2005 相似文献
4.
5.
The main components in plasminogen activation include plasminogen, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR), and plasminogen activator inhibitors-1 and –2 (PAI-1, PAI-2). These components are subject to extensive regulation and interactions with for example, pericellular adhesion molecules. Although uPA and tPA are quite similar in structure and have common inhibitors and physiological substrates, their physiological roles are distinct. Traditionally, the role of tPA has been in fibrinolysis and that of uPA in cell migration, especially in cancer cells. Recently several targets for tPA/plasmin have been found in neuronal tissues. The functional role of the PAIs is no longer simply to inhibit overexpressed plasminogen activators, and PAI-2 has an unidentified role in the regulation of cell death.Received 2 June 2004; received after revision 30 June 2004; accepted 20 July 2004 相似文献
6.
The Hedgehog family of growth factors activate a highly conserved signaling system for cell-cell communication that regulates
cell proliferation and differentiation during development. Abnormal activation of the Hedgehog pathway has been demonstrated
in a variety of human tumors, including those of the skin, brain, lung and digestive tract. Hedgehog pathway activity in these
tumors is required for cancer cell proliferation and tumor growth. Recent studies have uncovered the role for Hedgehog signaling
in advanced prostate cancer and demonstrated that autocrine signaling by tumor cells is required for proliferation, viability,
and invasive behavior. The level of Hedgehog activity correlates with the severity of the tumor and is both necessary and
sufficient for metastatic behavior. Blockade of Hedgehog signaling leads to tumor shrinkage and remission in preclinical tumor
xenograft models. Thus, Hedgehog signaling represents a novel pathway in prostate cancer that offers opportunities for prognostic
biomarker development, drug targeting and therapeutic response monitoring.
Received 18 August 2005; received after revision 30 September 2005; accepted 1 November 2005 相似文献
7.
Hadoke PW Macdonald L Logie JJ Small GR Dover AR Walker BR 《Cellular and molecular life sciences : CMLS》2006,63(5):565-578
The ability of glucocorticoids to directly alter arterial function, structure and the inflammatory response to vascular injury
may contribute to their well-established link with the development of cardiovascular disease. Recent studies have emphasised
the importance of tissue-specific regulation of glucocorticoid availability by the 11 β-hydroxysteroid dehydrogenase (11HSD)
isozymes, which inter-convert active glucocorticoids and their inactive metabolites. The expression of both type 1 and type
2 11HSDs in the arterial wall suggests that prereceptor metabolism of glucocorticoids may have a direct impact on vascular
physiology. Indeed there is evidence that 11HSDs influence glucocorticoid-mediated changes in vascular contractility, vascular
structure, the inflammatory response to injury and the growth of new blood vessels. Hence, inhibition of 11HSD isozymes may
provide a novel therapeutic target in vascular disease.
Received 19 September 2005; received after revision 1 November 2005; accepted 25 November 2005 相似文献
8.
Extracellular matrix and neuronal movement 总被引:1,自引:0,他引:1
P. Liesi 《Cellular and molecular life sciences : CMLS》1990,46(9):900-907
Summary During brain development, both neuronal migration and axon guidance are influenced by extracellular matrix molecules present in the environment of the migrating neuronal cell bodies and nerve fibers. Glial laminin is an extracellular matrix protein which these early brain cells preferentially attach to. Extracellular glycosaminoglycans are suggested to function in restricting neuronal cell bodies and axons from certain brain areas. Since laminin is deposited along the radial glial fibers and along the developing nerve pathways in punctate form, the punctate assemblies may be one of the key factors in routing the developing neurons in vivo. This review discusses the role of laminin in neuronal movement given the present concept of the extracellular matrix molecules and their proposed interactions. 相似文献
9.
Extracellular matrix and neuronal movement 总被引:3,自引:0,他引:3
P Liesi 《Experientia》1990,46(9):900-907
During brain development, both neuronal migration and axon guidance are influenced by extracellular matrix molecules present in the environment of the migrating neuronal cell bodies and nerve fibers. Glial laminin is an extracellular matrix protein which these early brain cells preferentially attach to. Extracellular glycosaminoglycans are suggested to function in restricting neuronal cell bodies and axons from certain brain areas. Since laminin is deposited along the radial glial fibers and along the developing nerve pathways in punctate form, the punctate assemblies may be one of the key factors in routing the developing neurons in vivo. This review discusses the role of laminin in neuronal movement given the present concept of the extracellular matrix molecules and their proposed interactions. 相似文献
10.
Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia
nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis
of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major
component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells,
synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various
E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation
into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone
and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit
both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss
several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD.
Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007 相似文献
11.
Talos IF Mian AZ Zou KH Hsu L Goldberg-Zimring D Haker S Bhagwat JG Mulkern RV 《Cellular and molecular life sciences : CMLS》2006,63(10):1106-1124
The introduction and development, over the last three decades, of magnetic resonance (MR) imaging and MR spectroscopy technology
for in vivo studies of the human brain represents a truly remarkable achievement, with enormous scientific and clinical ramifications.
These effectively non-invasive techniques allow for studies of the anatomy, the function and the metabolism of the living
human brain. They have allowed for new understandings of how the healthy brain works and have provided insights into the mechanisms
underlying multiple disease processes which affect the brain. Different MR techniques have been developed for studying anatomy,
function and metabolism. The primary focus of this review is to describe these different methodologies and to briefly review
how they are being employed to more fully appreciate the intricacies associated with the organ, which most distinctly differentiates
the human species from the other animal forms on earth.
Received 1 November 2005; received after revision 11 January 2006; accepted 25 January 2006 相似文献
12.
Nodal signals pattern vertebrate embryos 总被引:4,自引:0,他引:4
Vertebrate embryonic patterning requires several conserved inductive signals–including Nodal, Bmp, Wnt and Fgf signals. Nodal,
which is a member of the transforming growth factor β (TGFβ) superfamily, activates a signal transduction pathway that is
similar to that of other TGFβ members. Nodal genes, which have been identified in numerous vertebrate species, are expressed
in specific cell types and tissues during embryonic development. Nodal signal transduction has been shown to play a pivotal
role in inducing and patterning mesoderm and endoderm, and in regulating neurogenesis and left-right axis asymmetry. Antagonists,
which act at different steps in the Nodal signal transduction pathway, have been shown to tightly modulate the inductive activity
of Nodal.
Received 20 October 2005; received after revision 15 November 2005; accepted 25 November 2005 相似文献
13.
Galectin-7 总被引:4,自引:0,他引:4
Galectins are a family of animal lectins with an affinity for β-galactosides. They are differentially expressed by various
tissues and appear to be functionally multivalent, exerting a wide range of biological activities both during development
and in adult tissue. Galectin-7, a member of this family, contributes to different events associated with the differentiation
and development of pluristratified epithelia. It is also associated with epithelial cell migration, which plays a crucial
role in the re-epithelialization process of corneal or epidermal wounds. In addition, recent evidence indicates that galectin-7,
designated as the product of the p53-induced gene 1 (PIG1), is a regulator of apoptosis through JNK activation and mitochondrial
cytochrome c release. Defects in apoptosis constitute one of the major hallmarks of human cancers, and galectin-7 can act
as either a positive or a negative regulatory factor in tumour development, depending on the histological type of the tumour.
Received 30 October 2005; received after revision 15 November 2005; accepted 25 November 2005 相似文献
14.
Antiepileptic drugs and the developing brain 总被引:3,自引:0,他引:3
Kaindl AM Asimiadou S Manthey D Hagen MV Turski L Ikonomidou C 《Cellular and molecular life sciences : CMLS》2006,63(4):399-413
Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures
in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters
and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both
for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain
development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects
in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss
mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation
and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.
Received 3 August 2005; received after revision 13 October 2005; accepted 1 November 2005 相似文献
15.
Kallmann’s syndrome, a neuronal migration defect 总被引:1,自引:0,他引:1
Infertility and inability to smell are the phenotypical features of Kallmann’s syndrome (KS), a genetic disease which affects
1 in 10,000 males and 1 in 50,000 females, the majority of the cases being sporadic. The molecular pathogenesis of KS is complex
but mainly referable to the impairment of olfactory axon development and of the migration of gonadotropin-releasing hormone
(GnRH) neurons. Only two different genes have been identified so far as responsible for the disease: KAL1 and KAL2, encoding
anosmin-1 and fibroblast growth factor receptor 1 (FGFR1), respectively. In this review we focus our attention on insights
evoked by recent studies, which propose a new direct role for anosmin-1 in the migration GnRH neurons, and a fascinating hypothesis
of interactions between anosmin-1 and FGFR1 systems.
Received 23 December 2005; received after revision 31 May 2006; accepted 6 July 2006 相似文献
16.
Colorectal carcinoma: from tumorigenesis to treatment 总被引:10,自引:0,他引:10
Colorectal carcinoma (CRC) is a complicated and often fatal genetic disease. Fortunately, owing to rapid expansion of knowledge
and technology development in oncology, much progress has been made regarding the diagnosis, understanding of the molecular
genetics and malignant progression, as well as the novel regimens of CRC. In this review, we summarize the staging system,
the most critical genetic and epigenetic alterations, the pleiotropic effects of MMP-7, the controversial roles of Hedgehog
signaling, the intriguing involvement of thymosin β-4, and the possible contribution of the putative colon (cancer) stem cells
in CRC tumorigenesis. Current treatments as well as several potentially applicable therapeutic strategies for CRC are also
discussed.
Received 15 September 2005; received after revision 3 November 2005; accepted 25 November 2005 相似文献
17.
Jeon YH Heo YS Kim CM Hyun YL Lee TG Ro S Cho JM 《Cellular and molecular life sciences : CMLS》2005,62(11):1198-1220
Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.Received 30 November 2004; received after revision 24 January 2005; accepted 5 February 2005 相似文献
18.
Serine proteases have been shown to play a multifarious role in health and disease. As a result, there has been considerable
interest in the design and development of synthetic inhibitors of these enzymes. In view of their diverse roles in biological
processing events, one of the great challenges in such endeavours has been the need to produce compounds with exquisite selectivity.
Inhibitor design has been broadly guided by the use of either peptide- or heterocyclic-based compounds, designed to exploit
the known substrate specificity characteristics of individual enzymes. This review describes the thinking and strategies employed
in such efforts.
Received 8 August 2000; received after revision 16 November 2000; accepted 17 November 2000 相似文献
19.
The cytosolic glutathione S-transferases are a family of structurally homologous enzymes with multiple functions, including xenobiotic detoxification, clearance of oxidative stress products, and modulation of cell proliferation and apoptosis signaling pathways. This wideranging functional repertoire leads to several possible therapeutic uses for isoform-specific GST inhibitors. These inhibitors may be used, in principle, to modulate tumor cell drug resistance, as sensitizers to therapeutically directed oxidative stress, to enhance cell proliferation and to augment anti-malarial drugs. With increasing knowledge of GST structural and function, rational design strategies and mechanism-based inhibitors have been exploited successfully. However, design of isoform specificity remains a significant challenge in GST inhibitor development. Strategies for further inhibitor design and their possible limitations, along with potential therapeutic uses, are summarized.Received 24 November 2004; received after revision 12 January 2005; accepted 11 February 2005 相似文献
20.
Wikenheiser-Brokamp KA 《Cellular and molecular life sciences : CMLS》2006,63(7-8):767-780
The retinoblastoma (Rb) gene was identified as the first tumor suppressor gene two decades ago. Since this initial discovery,
it has become clear that deregulated Rb function constitutes a hallmark of human malignancies. Rb is a well-established regulator
of the cell cycle. Rb has also been implicated in playing a role in a wide variety of cellular processes including DNA repair,
cellular senescence, cell fate determination and apoptosis. Animals lacking Rb and/or its family members p107 and p130 have
led scientists to uncover new and exciting roles for this protein family in development as well as tumor suppression. The
ability to ablate Rb in a temporal and cell-type-specific manner has offered further, often unexpected, insights into Rb function.
This review summarizes the phenotypic consequences of Rb family ablation in mice, and discusses how these findings contribute
to the increasingly complex picture of Rb family function in development and tumor suppression.
Received 11 October 2005; received after revision 16 November 2005; accepted 28 November 2005 相似文献