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1.
Because tumors require a vascular supply for their survival and growth, angiogenesis is considered an important therapeutic target in most human cancers including cancer of the central nervous system. Antiangiogenic therapy has focused on inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway. VEGF pathway-targeted drugs have shown therapeutic efficacy in several CNS tumors and have been tried most frequently in glioblastoma. These therapies, however, have been less effective than anticipated as some patients do not respond to therapy and some receive only modest benefit. Underlying this suboptimal response are multiple mechanisms of drug resistance involving changes in both tumor cells and their microenvironment. In this review, we discuss the multiple proposed mechanisms by which neurological tumors evolve to become resistant to antiangiogenic therapies. A better understanding of these mechanisms, their context, and their interplay will likely facilitate improvements in pharmacological strategies for the targeted treatment of neurological tumors. 相似文献
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T. Hubert S. Grimal P. Carroll A. Fichard-Carroll 《Cellular and molecular life sciences : CMLS》2009,66(7):1223-1238
Collagens are extracellular proteins characterized by a structure in triple helices. There are 28 collagen types which differ
in size, structure and function. Their architectural and functional roles in connective tissues have been widely assessed.
In the nervous system, collagens are rare in the vicinity of the neuronal soma, occupying mostly a “marginal” position, such
as the meninges, the basement membranes and the sensory end organs. In neural development, however, where various ECM molecules
are known to be determinant, recent studies indicate that collagens are no exception, participating in axonal guidance, synaptogenesis
and Schwann cell differentiation. Insights on collagens function in the brain have also been derived from neural pathophysiological
conditions. This review summarizes the significant advances which underscore the function and importance of collagens in the
nervous system.
Received 09 September 2008; received after revision 24 October 2008; accepted 28 October 2008 相似文献
4.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
5.
Rosenstiel P Jacobs G Till A Schreiber S 《Cellular and molecular life sciences : CMLS》2008,65(9):1361-1377
NOD-like receptors (NLRs) comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels
mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. Genetic variants in
NLR genes have been associated with complex chronic inflammatory barrier diseases (e.g. Crohn disease, bronchial asthma). In
this review, we focus on the molecular pathophysiology of NLRs in the context of chronic inflammatory diseases and pinpoint
recent advances in the evolutionary understanding of NLR biology. We propose that the field of NLRs may serve as a prototype
for how a comprehensive understanding of an element of the immunological barrier will eventually lead to the development of
targeted diagnostic, therapeutic and/or preventive strategies.
Received 29 October 2007; received after revision 10 December 2007; accepted 19 December 2007 相似文献
6.
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
7.
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
8.
N. Asano 《Cellular and molecular life sciences : CMLS》2009,66(9):1479-1492
A large number of compounds mimicking the structures of monosaccharides or oligosaccharides have been discovered from natural
sources. Such sugar mimics inhibit carbohydrate-degrading enzymes because of a structural resemblance to the sugar moiety
of the natural substrate. Carbohydrate-degrading enzymes are involved in a wide range of important biological processes, such
as intestinal digestion, posttranslational processing of the sugar chain of glycoproteins, their quality control mechanisms,
lysosomal catabolism of glycoconjugates, and some viral infections. It has now been realized that inhibitors of the enzymes
have enormous therapeutic potential in diabetes and lysosomal storage disorders. In this review, the general bioactivity,
current applications, and the prospects for new therapeutic applications are described.
Received 27 August 2008; received after revision 08 November 2008; accepted 03 December 2008 相似文献
9.
T-cell signal transduction and the role of protein kinase C 总被引:3,自引:0,他引:3
The T lymphocyte has a vital part to play in maintaining the host response to bacterial and viral infection and also appears
to play a key pathological role in autoimmune diseases such as rheumatoid arthritis. In this review, we summarize the signalling
pathways which trigger antigen-driven T-cell proliferation and examine the evidence which suggests that protein kinase C (PKC)
is fundamental to this process. Finally, we discuss the therapeutic potential that PKC inhibitors may have in the treatment
of autoimmune disease.
Received 31 March 1998; received after revision 19 May 1998; accepted 19 May 1998 相似文献
10.
Dubin G 《Cellular and molecular life sciences : CMLS》2005,62(6):653-669
Studies of proteinaceous cysteine protease inhibitors originated with the discovery of cystatins in the 1960s. Since that time, a rich and fascinating world of proteins that control and regulate a multitude of important physiological processes, ranging from the basics of protein turnover to development and brain function, has been uncovered. Failures in such important and complex systems inevitably lead to pathologies. Many threatening diseases such as cancer or neurological disorders, to mention only some, are attributed to deregulation of proteaseinhibitor balance. Moreover, important aspects of infection pathology and host defense rely on proteolysis and protease inhibition. Recent advances in the field of protease inhibitors have drawn attention to the possible use of this collected knowledge to control related pathological processes. This review attempts to familiarize the reader with proteinaceous cysteine protease inhibitors by providing an overview of current knowledge. The work primarily highlights biological processes in which the inhibitors are involved and focuses on pathologies resulting from aberrant protease-inhibitor balance, pointing out emerging possibilities for their correction.Received 11 October 2004; received after revision 29 November 2004; accepted 6 December 2004 相似文献
11.
Mitogenic signals stimulate cell division by activating cyclin/cyclin-dependent kinase (CDK) complexes. Their timely regulation
ensures proper cell cycle progression. It is therefore not surprising that cyclin/CDK complexes are integrators of multiple
signals from both the extracellular environment and intracellular cues. Important regulators of cyclin/CDKs are the CDK inhibitors
that have attracted attention due to their association with disease. p27KIP1 is a CDK inhibitor that controls CDK activity throughout the cell cycle. As a CDK inhibitor, p27KIP1 has tumor suppressor activity. Besides CDKs, p27KIP1 regulates additional cellular processes, including cell motility, some of which seem to mediate oncogenic activities of p27KIP1. These activities of p27KIP1 are regulated through multiple phosphorylation sites, targeted by several signal transduction pathways. Understanding functions
and regulation of p27KIP1 will be important to determine which isoform of p27KIP1 has anti- or pro-tumorigenic activities. Such knowledge might be of prognostic value and may offer novel therapeutic windows.
Received 26 May 2008; accepted 17 June 2008 相似文献
12.
A. C. S. Souza S. Azoubel K. C. S. Queiroz M. P. Peppelenbosch C. V. Ferreira 《Cellular and molecular life sciences : CMLS》2009,66(7):1140-1153
Reversible tyrosine phosphorylation is a key posttranslational regulatory modification of proteins in all eukaryotic cells
in normal and pathological processes. Recently a pivotal janus-faced biological role of the low molecular weight protein tyrosine
phosphatase (LMWPTP) has become clear. On the one hand this enzyme is important in facilitating appropriate immune responses
towards infectious agents, on the other hand it mediates exaggerated inflammatory responses toward innocuous stimuli. The
evidence that LMWPTP plays a role in oncological processes has added a promising novel angle. In this review we shall focus
on the regulation of LMWPTP enzymatic activity of signaling pathways of different immunological cells, the relation between
genetic polymorphism of LMWPTP and predisposition to some type of inflammatory disorders and the contribution of this enzyme
to cancer cell onset, growth and migration. Therefore, the LMWPTP is an interesting target for pharmacological intervention,
thus modifying both inappropriate cellular immune responses and cancer cell aggressiveness.
Received 15 August 2008; received after revision 06 October 2008; accepted 14 October 2008 相似文献
13.
Victor Van Puyenbroeck Kurt Vermeire 《Cellular and molecular life sciences : CMLS》2018,75(9):1541-1558
Proteins routed to the secretory pathway start their journey by being transported across biological membranes, such as the endoplasmic reticulum. The essential nature of this protein translocation process has led to the evolution of several factors that specifically target the translocon and block translocation. In this review, various translocation pathways are discussed together with known inhibitors of translocation. Properties of signal peptide-specific systems are highlighted for the development of new therapeutic and antimicrobial applications, as compounds can target signal peptides from either host cells or pathogens and thereby selectively prevent translocation of those specific proteins. Broad inhibition of translocation is also an interesting target for the development of new anticancer drugs because cancer cells heavily depend on efficient protein translocation into the endoplasmic reticulum to support their fast growth. 相似文献
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Protein kinase C (PKC) is an important signaling molecule in the heart, but its targets remain unclear. Using a PKC substrate
antibody, we detected a 40-kDa phosphorylated cardiac protein that was subsequently identified by tandem mass spectroscopy
as muscle creatine kinase (M-CK) with phosphorylation at serine 128. The forward reaction using ATP to generate phosphocreatine
was reduced, while the reverse reaction using phosphocreatine to generate ATP was increased following dephosphorylation of
immunoprecipitated M-CK with protein phosphatase 2A (PP2A) or PP2C. Despite higher PKC levels in diabetic hearts, decreased
phosphorylation of M-CK was more prominent than the reduction in its expression. Changes in CK activity in diabetic hearts
were similar to those found following dephosphorylation of M-CK from control hearts. The decrease in phosphorylation may act
as a compensatory mechanism to maintain CK activity at an appropriate level for cytosolic ATP regeneration in the diabetic
heart.
Received 15 September 2008; received after revision 30 September 2008; accepted 13 October 2008 相似文献
15.
David M. Wilson III Anton Simeonov 《Cellular and molecular life sciences : CMLS》2010,67(21):3621-3631
APE1 is a multifunctional protein that possesses several nuclease activities, including the ability to incise at apurinic/apyrimidinic
(AP) sites in DNA or RNA, to excise 3′-blocking termini from DNA ends, and to cleave at certain oxidized base lesions in DNA.
Pre-clinical and clinical data indicate a role for APE1 in the pathogenesis of cancer and in resistance to DNA-interactive
drugs, particularly monofunctional alkylators and antimetabolites. In an effort to improve the efficacy of therapeutic compounds,
such as temozolomide, groups have begun to develop high-throughput screening assays and to identify small molecule inhibitors
against APE1 repair nuclease activities. It is envisioned that such inhibitors will be used in combinatorial treatment paradigms
to enhance the efficacy of DNA-interactive drugs that introduce relevant cytotoxic DNA lesions. In this review, we summarize
the current state of the efforts to design potent and selective inhibitors against APE1 AP site incision activity. 相似文献
16.
C. Akgul 《Cellular and molecular life sciences : CMLS》2009,66(8):1326-1336
Resistance to apoptosis is a common challenge in human malignancies contributing to both progress of cancer and resistance
to conventional therapeutics. Abnormalities in a variety of cell intrinsic and extrinsic molecular mechanisms cooperatively
promote tumor formation. Therapeutic approaches that specifically target components of these molecular mechanisms are getting
widespread attention. Mcl-1 is a highly expressed pro-survival protein in human malignancies and its cellular expression is
tightly regulated via multiple mechanisms. Mcl-1 differs from other members of the Bcl-2 family in having a very short half-life. So inhibition
of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible
to apoptosis and provide an opportunity to combat several types of cancers. This review summarizes the current knowledge on
the regulation of Mcl-1 expression and discusses the alternative approaches targeting Mcl-1 in human cancer cells whose survivals
mainly depend on Mcl-1.
Received 6 October 2008; received after revision 21 October 2008; accepted 10 November 2008 相似文献
17.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. More than one-third of MCC patients
will die from this cancer, making it twice as lethal as malignant melanoma. Despite the fact that MCC is still a very rare
tumor, its incidence is rapidly increasing; the American Cancer Society estimates for 2008 almost 1 500 new cases in the USA.
These clinical observations are especially disturbing as the pathogenesis of MCC is not yet fully understood; however, a number
of recent reports contribute to a better understanding of its pathogenesis. Here we describe findings regarding the role of
Wnt, MAPK and Akt signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor network in MCC. Most important,
and possibly with high impact on future therapeutic approaches is the demonstration that a polyomavirus has frequently integrated
in the genome of the MCC cells prior to tumor development.
Received 12 August 2008; received after revision 06 October 2008; accepted 22 October 2008 相似文献
18.
阿尔茨海默病(Alzheimer's disease,AD)是老年人最常见的神经系统退行性疾病.经β-和γ-分泌酶切割形成的β淀粉样蛋白(amyloid-beta,Aβ)与AD的发生密切相关.γ-分泌酶是一个含有早老素的复合蛋白体,作为Aβ代谢的关键酶,它是治疗AD的潜力的靶点.在过去20年里,药物研究且发现了能抑制或调节γ-分泌酶的小分子化合物,部分化合物已经进入临床研究.本文就Aβ的形成、γ-分泌酶的结构及目前γ-分泌酶的抑制剂、调节剂的研究进展作一综述介绍. 相似文献
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Sepsis is a common and serious medical condition caused by hemorrhage, trauma, or abdominal surgery. Despite new understanding
and much progress in therapies that specifically interfere with an interesting target, sepsis remains the leading causes of
death in critically ill patients. Various therapies have been studied, but the majority of these treatments fail in clinical
trials. It is clear that all septic patients exhibit coagulation abnormalities. These abnormalities range from subtle to marked
activation of coagulation system, and finally to fulminant DIC. Studies confirmed that carbon monoxide has important cytoprotective
function and anti-inflammatory properties. Until now, the question of whether CO plays a critical role in improving the coagulation
system and then decreasing mortality during sepsis has not yet been definitely answered. Attempts to confirm this strategy
may lead to new directions in the study of treatment of sepsis and the development of a novel agent for this disorder.
Received 13 August 2008; received after revision 29 October 2008; accepted 17 November 2008 相似文献