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1.
Monocytes and their pathophysiological role in Crohn’s disease 总被引:1,自引:1,他引:0
Zhou L Braat H Faber KN Dijkstra G Peppelenbosch MP 《Cellular and molecular life sciences : CMLS》2009,66(2):192-202
Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the
other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity
is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate
immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments
in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role
in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of
monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation
of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte
functions need to be taken into account.
Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008 相似文献
2.
The identification of the aspartic protease BACE1 (β-secretase) was a defining event in research aimed at understanding the
molecular mechanisms that underlie Alzheimer’s disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting
step in the production of amyloid-β (Aβ) the principal component of plaque pathology in AD, the excessive production of which
is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that
genetic deletion of BACE1 completely abolishes Aβ production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing
its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target
in blocking aberrant Aβ production in AD.
Received 15 May 2008; received after revision 13 June 2008; accepted 18 June 2008 相似文献
3.
Nabeshima Y 《Cellular and molecular life sciences : CMLS》2008,65(20):3218-3230
The traditional view of calcium homeostasis is that it is maintained by two essential reactions. First, changes in extracellular
Ca2+ are sensed in several distinct cell types, stimulating the secretion of parathyroid hormone (PTH), 1,25(OH)2 D and calcitonin in response to the body’s requirement. Second, these calcitropic hormones then act on the calcium-translocating
cells of the kidney, bone, and intestine to restore calcium balance. Recent progress indicates that α-Klotho and fibroblast
growth factor (FGF) 23 are key players that integrate the multi-step regulatory system of calcium homeostasis that rapidly
adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological
range. α-Klotho and FGF23 are also found to be major players in the regulatory system of phosphate homeostasis. Here, the
demonstration of the molecular functions of α-Klotho and FGF23 has recently given new insight into the field of calcium and
phosphate homeostasis.
Received 3 April 2008; received after revision 23 May 2008; accepted 5 June 2008 相似文献
4.
Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates.
The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular
chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating
proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence
of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer’s and Parkinson’s). In this review, the literature
on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability
of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its
implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.
Received 13 June 2008; received after revision 29 July 2008; accepted 05 August 2008 相似文献
5.
Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A ‘recommended’
human diet contains significant quantities of polyphenolics, as they have long been assumed to be ‘antioxidants’ that scavenge
excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also
have ‘indirect’ antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence
for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive
or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last
2 – 3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and
metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects
and regulatory effects on energy metabolism and gut health.
Received 14 May 2007; received after revision 27 June 2007; accepted 24 July 2007 相似文献
6.
Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy
for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent
γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently,
transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial
knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive
to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase
is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation,
abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with
an emphasis on the functional role of presenilins in cell biology.
Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008 相似文献
7.
B. Schäfer C. Götz J. Dudek A. Hessenauer U. Matti M. Montenarh 《Cellular and molecular life sciences : CMLS》2009,66(2):339-349
Protein kinase CK2 is a highly conserved serine/threonine kinase that is ubiquitously expressed in eukaryotic cells. CK2 is
a constitutively active tetrameric enzyme composed of two catalytic α and/or α’-subunits and two regulatory β-subunits. There
is increasing evidence that the individual subunits may have independent functions and that they are asymmetrically distributed
inside the cell. To gain a better understanding of the functions of the individual subunits, we employed a yeast-two-hybrid
screen with CK2α and CK2α’. We identified the motor neuron protein KIF5C as a new binding partner for CK2. The interaction
found in the yeast-two-hybrid screen was confirmed by co-sedimentation analysis on a sucrose density gradient and by co-immunoprecipitation
analysis. Pull-down experiments and surface plasmon resonance spectrometry revealed a direct binding of KIF5C to CK2α’. Co-localization
studies with neuroblastoma cells, bone marrow and with primary neurons confirmed the biochemical analysis that KIF5C preferentially
bound to CK2α’.
Received 8 August 2008; received after revision 3 November 2008; accepted 4 November 2008 相似文献
8.
E. L. Portiansky P. H. González R. P. Laguens 《Cellular and molecular life sciences : CMLS》1996,52(6):605-607
The immunization of biungulate animals with killed foot-and-mouth disease virus (FMDV) requires periodic vaccinations due to a low vaccine immunogenicity. Therefore, FMDV antigens need to be combined with adjuvants such as aluminum hydroxide, saponin or oil emulsions. Animal handling for periodic inoculations, and the repeated doses of vaccines that have to be administered increase the commercialization costs. Moreover, the use of adjuvants may induce adverse effects.In the present work we show that it is possible to increase the life span of neutralizing antibodies in serum when a single dose of cyclophosphamide (Cy) is administered four days before vaccination with aluminum hydroxidesaponin FMDV vaccine. 相似文献
9.
It has now been more than ten years since the discovery of the major apoptotic nuclease, DNA fragmentation factor (DFF), also
known as caspaseactivated DNase (CAD). Here we review the recent literature that has uncovered new insight into DFF’s regulation,
and both its positive and negative roles in human disease. Cells from mice deficient in DFF still undergo apoptotic death
without significant cellautonomous DNA degradation. Their corpses’ genomes are subsequently degraded by lysosomal DNase II
after phagocytosis. However,DFF-deficient mice are more susceptible to cancer. Indeed, several different cancers in humans
are associated with defects in DFF expression and it has been proposed that DFF is a p53-independent tumor suppressor. Negative
aspects of DFF expression include contributing to susceptibility to acquire systemic lupus erythematosus, to chromosomal translocations
that result in mixed lineage leukemias, and in the possible spreading of oncogenes and HIV due to horizontal gene transfer.
Received 06 August 2008; received after revision 03 September 2008; accepted 09 September 2008 相似文献
10.
Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action 总被引:3,自引:0,他引:3
Montecucco C Gutiérrez JM Lomonte B 《Cellular and molecular life sciences : CMLS》2008,65(18):2897-2912
A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors
and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which
is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation
which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular
junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms
of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.
Received 05 March 2008; received after revision 08 April 2008; accepted 29 April 2008 相似文献
11.
Poulsen LR López-Marqués RL Palmgren MG 《Cellular and molecular life sciences : CMLS》2008,65(20):3119-3125
Our understanding of flippase-mediated lipid translocation and membrane vesiculation, and the involvement of P-type ATPases
in these processes is just beginning to emerge. The results obtained so far demonstrate significant complexity within this
field and point to major tasks for future research. Most importantly, biochemical characterization of P4-ATPases is required in order to clarify whether these transporters indeed are capable of catalyzing transmembrane phospholipid
flipping. The β-subunit of P4-ATPases shows unexpected similarities between the β- and γ-subunits of the Na+/K+-ATPase. It is likely that these proteins provide a similar solution to similar problems, and might have adopted similar structures
to accomplish these tasks. No P4-ATPases have been identified in the endoplasmic reticulum and it remains an intriguing possibility that, in this compartment,
P5A-ATPases are functional homologues of P4-ATPases.
Received 19 June 2008; received after revision 31 July 2008; accepted 15 August 2008 相似文献
12.
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
13.
AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism 总被引:1,自引:0,他引:1
Witczak CA Sharoff CG Goodyear LJ 《Cellular and molecular life sciences : CMLS》2008,65(23):3737-3755
The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator
of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this
review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include
the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization
in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known
upstream kinases, LKB1, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological
agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate
AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle.
Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008 相似文献
14.
Poelarends GJ Veetil VP Whitman CP 《Cellular and molecular life sciences : CMLS》2008,65(22):3606-3618
Tautomerase superfamily members have an amino-terminal proline and a β–α–β fold, and include 4-oxalocrotonate tautomerase
(4-OT), 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cis-CaaD, respectively), malonate semialdehyde decarboxylase (MSAD), and macrophage migration inhibitory factor (MIF), which
exhibits a phenylpyruvate tautomerase (PPT) activity. Pro-1 is a base (4-OT, CHMI, the PPT activity of MIF) or an acid (CaaD,
cis-CaaD, MSAD). Components of the catalytic machinery have been identified and mechanistic hypotheses formulated. Characterization
of new homologues shows that these mechanisms are incomplete. 4-OT, CaaD, cis-CaaD, and MSAD also have promiscuous activities with a hydratase activity in CaaD, cis-CaaD, and MSAD, PPT activity in CaaD and cis-CaaD, and CaaD and cis-CaaD activities in 4-OT. The shared promiscuous activities provide evidence for divergent evolution from a common ancestor,
give hints about mechanistic relationships, and implicate catalytic promiscuity in the emergence of new enzymes.
Received 22 May 2008; received after revision 20 June 2008; accepted 02 July 2008 相似文献
15.
Katona RL Sinkó I Holló G Szucs KS Praznovszky T Kereso J Csonka E Fodor K Cserpán I Szakál B Blazsó P Udvardy A Hadlaczky G 《Cellular and molecular life sciences : CMLS》2008,65(23):3830-3838
Mammalian artificial chromosomes (MACs) are safe, stable, non-integrating genetic vectors with almost unlimited therapeutic
transgene-carrying capacity. The combination of MAC and stem cell technologies offers a new strategy for stem cell-based therapy,
the efficacy of which was confirmed and validated by using a mouse model of a devastating monogenic disease, galactocerebrosidase
deficiency (Krabbe’s disease). Therapeutic MACs were generated by sequence-specific loading of galactocerebrosidase transgenes
into a platform MAC, and stable, pluripotent mouse embryonic stem cell lines were established with these chromosomes. The
transgenic stem cells were thoroughly characterized and used to produce chimeric mice on the mutant genetic background. The
lifespan of these chimeras was increased twofold, verifying the feasibility of the development of MAC-stem cell systems for
the delivery of therapeutic genes in stem cells to treat genetic diseases and cancers, and to produce cell types for cell
replacement therapies.
Received 29 July 2008; received after revision 22 September 2008; accepted 24 September 2008 相似文献
16.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
17.
18.
Lage H 《Cellular and molecular life sciences : CMLS》2008,65(20):3145-3167
Although various mechanisms involved in anticancer multidrug resistance (MDR) can be identified, it remains a major problem
in oncology. Beyond that, the introduction of new “targeted” drugs have not solved the problem. On the contrary, it has been
demonstrated that the “classical” MDR-associated mechanisms are similar or identical to those causing resistance to these
novel agents. These mechanisms include the enhanced activity of drug pumps, i.e. ABC or alternative transporters; modulation
of cellular death pathways; alteration and repair of target molecules; and various less common mechanisms. Together they build
a complex network of cellular pathways and molecular mechanisms mediating an individual MDR phenotype. Although the application
of new high throughput “-omics” technologies have identified multiple new gene-/protein expression signatures or factors associated
with drug resistance, so far none of these findings has been useful for creating improved diagnostic assays, for prediction
of individual therapy response, or for development of updated chemosensitizers.
Received 05 March 2008; received after revision 21 May 2008; accepted 23 May 2008 相似文献
19.
Li R 《Cellular and molecular life sciences : CMLS》2007,64(23):3044-3058
Cytokinesis is a crucial step in cell proliferation, and remarkably, it is also an important mechanism for developmental regulation
in the generation of diverse cell types in eukaryotic organisms. Successful cytokinesis relies on the assembly and activation
of an actomyosin-based contractile ring and membrane deposition/fusion in a spatially and temporally precise manner. As such,
the molecular pathways governing cytokinesis are highly complex, involving a large number of components forming intricate
interactive networks. The complexity of this system, however, may have also provided a rich platform for evolutionary ‘tinkering’
to achieve specific morphogenetic and developmental outcomes. Furthermore, failed or altered cytokinesis appears to contribute
to the development of cancer in unexpected ways.
Received 25 June 2007; received after revision 20 July 2007; accepted 16 August 2007 相似文献
20.
Molecular Physiology of Mammalian Glucokinase 总被引:1,自引:1,他引:0
Iynedjian PB 《Cellular and molecular life sciences : CMLS》2009,66(1):27-42
The glucokinase (GCK) gene was one of the first candidate genes to be identified as a human “diabetes gene". Subsequently,
important advances were made in understanding the impact of GCK in the regulation of glucose metabolism. Structure elucidation
by crystallography provided insight into the kinetic properties of GCK. Protein interaction partners of GCK were discovered.
Gene expression studies revealed new facets of the tissue distribution of GCK, including in the brain, and its regulation
by insulin in the liver. Metabolic control analysis coupled to gene overexpression and knockout experiments highlighted the
unique impact of GCK as a regulator of glucose metabolism. Human GCK mutants were studied biochemically to understand disease
mechanisms. Drug development programs identified small molecule activators of GCK as potential antidiabetics. These advances
are summarized here, with the aim of offering an integrated view of the role of GCK in the molecular physiology and medicine
of glucose homeostasis.
Received 11 June 2008; received after revision 18 July 2008; accepted 30 July 2008 相似文献