共查询到20条相似文献,搜索用时 15 毫秒
1.
Towards progress on DNA vaccines for cancer 总被引:2,自引:0,他引:2
Lowe DB Shearer MH Jumper CA Kennedy RC 《Cellular and molecular life sciences : CMLS》2007,64(18):2391-2403
Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived
immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA
represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response
in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed
well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not
impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing
DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid
DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response
while also targeting tumor evasion mechanisms.
Received 2 April 2007; received after revision 14 May 2007; accepted 21 May 2007 相似文献
2.
Infection of bacteria triggers innate immune defense reactions in Drosophila. So far, the only bacterial component known to be recognized by the insect innate immune system is peptidoglycan, one of
the most abundant constituents of the bacterial cell wall. Insects use peptidoglycan recognition proteins to detect peptidoglycan
and to activate innate immune responses. Such specialized peptidoglycan receptors appear to have evolved from phage enzymes
that hydrolyze bacterial cell walls. They are able to bind specific peptidoglycan molecules with distinct chemical moieties
and activate innate immune pathways by interacting with other signaling proteins. Recent X-ray crystallographic studies of
the peptidoglycan recognition proteins LCa, and LCx bound to peptidoglycan have provided structural insights into recognition
of peptidoglycan and activation of innate immunity in insects.
Received 28 December 2006; received after revision 2 February 2007; accepted 21 February 2007 相似文献
3.
Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development
of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs
and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular
mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to
increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress
in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery
as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.
Received 8 August 2007; received after revision 19 September 2007; accepted 2 October 2007 相似文献
4.
Shin JM Vagin O Munson K Kidd M Modlin IM Sachs G 《Cellular and molecular life sciences : CMLS》2008,65(2):264-281
Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration;
therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor
were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell
hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are
the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities.
Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of
a novel class of agents, the acid pump antagonists.
Received 30 May 2007; received after revision 15 August 2007; accepted 13 September 2007 相似文献
5.
de Wit PJ 《Cellular and molecular life sciences : CMLS》2007,64(21):2726-2732
Plants have an innate immunity system to defend themselves against pathogens. With the primary immune system, plants recognize
microbe-associated molecular patterns (MAMPs) of potential pathogens through pattern recognition receptors (PRRs) that mediate
a basal defense response. Plant pathogens suppress this basal defense response by means of effectors that enable them to cause
disease. With the secondary immune system, plants have gained the ability to recognize effector-induced perturbations of host
targets through resistance proteins (RPs) that mediate a strong local defense response that stops pathogen growth. Both primary
and secondary immune responses in plants depend on germ line-encoded PRRs and RPs. During induction of local immune responses,
systemic immune responses also become activated, which predispose plants to become more resistant to subsequent pathogen attacks.
This review gives an update on recent findings that have enhanced our understanding of plant innate immunity and the arms
race between plants and their pathogens.
Received 24 June 2007; received after revision 18 July 2007; accepted 15 August 2007 相似文献
6.
Regulatory mechanisms of mitogen-activated kinase signaling 总被引:5,自引:1,他引:4
MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction and play essential roles in various
physiological processes. There are three main families of MAPKs in mammals, whose functions are regulated by activators, inactivators,
substrates and scaffolds, which together form delicate signaling cascades in response to different extracellular or intracellular
stimulation. MAPK signaling is tightly regulated so that optimal biological activities are achieved and health is maintained.
However, how the specificity of the signaling flow along each cascade is achieved is still relatively unclear. In this review,
we summarize recent advances in understanding the regulation of MAPK cascades and the roles of MAP kinases and their regulators
in development and in immune responses.
Received 11 January 2007; received after revision 31 May 2007; accepted 5 July 2007 相似文献
7.
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
8.
The innate immunity of the central nervous system in chronic pain: The role of Toll-like receptors 总被引:1,自引:0,他引:1
Toll-like receptors (TLRs) are a family of pattern recognition receptors that mediate innate immune responses to stimuli from
pathogens or endogenous signals. Under various pathological conditions, the central nervous system (CNS) mounts a well-organized
innate immune response, in which glial cells, in particular microglia, are activated. Further, the innate immune system has
emerged as a promising target for therapeutic control of development and persistence of chronic pain. Especially, microglial
cells respond to peripheral and central infection, injury, and other stressor signals arriving at the CNS and initiate a CNS
immune activation that might contribute to chronic pain facilitation. In the orchestration of this limited immune reaction,
TLRs on microglia appear to be most relevant in triggering and tailoring microglial activation, which might be a driving force
of chronic pain. New therapeutic approaches targeting the CNS innate immune system may achieve the essential pharmacological
control of chronic pain.
Received 21 November 2006; received after revision 8 January 2007; accepted 7 February 2007 相似文献
9.
Eosinophils are traditionally thought to form part of the innate immune response against parasitic helminths acting through
the release of cytotoxic granule proteins. However, they are also a central feature in asthma. From their development in the
bone marrow to their recruitment to the lung via chemokines and cytokines, they form an important component of the inflammatory
milieu observed in the asthmatic lung following allergen challenge. A wealth of studies has been performed in both patients
with asthma and in mouse models of allergic pulmonary inflammation to delineate the role of eosinophils in the allergic response.
Although the long-standing association between eosinophils and the induction of airway hyper-responsiveness remains controversial,
recent studies have shown that eosinophils may also promote airway remodelling. In addition, emerging evidence suggests that
the eosinophil may also serve to modulate the immune response. Here we review the highly co-ordinated nature of eosinophil
development and trafficking and the evolution of the eosinophil as a multi-factoral leukocyte with diverse functions in asthma.
Received 6 December 2006; received after revision 11 January 2007; accepted 15 February 2007 相似文献
10.
Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat
has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients
following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to
heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability
to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles,
making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms
responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.
Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007 相似文献
11.
We summarize the clinical presentation and molecular basis of a unique group of congenital immunodeficiency disorders in which
defects in immune tolerance mechanisms result in severe autoimmunity. Patients with severe, familial forms of multi-organ
autoimmunity have been recognized and clinically described for more than 40 years (Clin Exp Immunol 1: 119–128, 1966; Clin Exp Immunol 2: 19–30, 1967). Some are characterized primarily by autoimmunity and others by autoimmunity combined with susceptibility to specific infectious
organisms. The first mechanistic understanding of these disorders began to emerge approximately 10 years ago with the initial
identification of causative genes. As a result, our understanding of how immune tolerance is established and maintained in
humans has expanded dramatically. Data generated over the last 3–4 years including identification of additional gene defects
and functional characterization of each identified gene product in human and animal models have added clarity. This, in turn,
has improved our ability to diagnose and effectively treat these severe, life-threatening disorders. Inherited disorders characterized
by immune dysregulation have dramatically expanded our understanding of immune tolerance mechanisms in humans. Recognition
and diagnosis of these disorders in the clinic allows timely initiation of life-saving therapies that may prevent death or
irreversible damage to vital organs. 相似文献
12.
Williams AE 《Cellular and molecular life sciences : CMLS》2008,65(4):545-562
MicroRNAs (miRNAs) are a recently discovered family of small regulatory molecules that function by modulating protein production.
There are approximately 500 known mammalian miRNA genes, and each miRNA may regulate hundreds of different protein-coding
genes. Mature miRNAs bind to target mRNAs in a protein complex known as the miRNA-induced silencing complex (miRISC), sometimes
referred to as the miRNP (miRNA-containing ribonucleoprotein particles), where mRNA translation is inhibited or mRNA is degraded.
These actions of miRNAs have been shown to regulate several developmental and physiological processes including stem cell
differentiation, haematopoiesis, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism
and the immune response. Furthermore, aberrant expression has been implicated in a number of diseases including cancer and
heart disease. The role of miRNAs in these developmental, physiological and pathological processes will be reviewed.
Received 3 August 2007; received after revision 3 October 2007; accepted 5 October 2007 相似文献
13.
Untangling the molecular nature of sperm-egg interactions is fundamental if we are to understand fertilization. These phenomena
have been studied for many years using biochemical approaches such as antibodies and ligands that interact with sperm or with
eggs and their vestments. However, when homologous genetic recombination techniques were applied, most of the phenotypic factors
of the gene-manipulated animals believed “essential” for fertilization were found to be dispensable. Of course, all biological
systems contain redundancies and compensatory mechanisms, but as a whole the old model of fertilization clearly requires significant
modification. In this review, we use the results of gene manipulation experiments in animals to propose the basis for a new
vision.
Received 26 January 2007; received after revision 7 March 2007; accepted 17 April 2007 相似文献
14.
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
15.
Bencherif M Lippiello PM Lucas R Marrero MB 《Cellular and molecular life sciences : CMLS》2011,68(6):931-949
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis,
psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated
inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial
changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines
such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting
alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines.
This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7
receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach
could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory
components. 相似文献
16.
Hurtaud C Gelly C Chen Z Lévi-Meyrueis C Bouillaud F 《Cellular and molecular life sciences : CMLS》2007,64(14):1853-1860
Uncoupling protein 2 (UCP2) belongs to a family of transporters/exchangers of the mitochondrial inner membrane. Using cell
lines representing natural sites of UCP2 expression (macrophages, colonocytes, pancreatic beta cells), we show that UCP2 expression
is stimulated by glutamine at physiological concentrations. This control is exerted at the translational level. We demonstrate
that the upstream open reading frame (ORF1) in the 5’ untranslated region (5’UTR) of the UCP2 mRNA is required for this stimulation
to take place. Cloning of the 5’ UTR of the UCP2 mRNA in front of a GFP cDNA resulted in a reporter gene with which GFP expression
could be induced by glutamine. An effect of glutamine on translation of a given mRNA has not been identified before, and this
is the first evidence for a link between UCP2 and glutamine, an amino acid oxidized by immune cells or intestinal epithelium
and playing a role in the control of insulin secretion.
Received 26 January 2007; received after revision 16 April 2007; accepted 8 May 2007
C. Hurtaud, C. Gelly: These authors contributed equally to this work. 相似文献
17.
We analyze the behavior of experts who quote forecasts for monthly SKU‐level sales data, where we compare data before and after the moment that experts received different kinds of feedback on their behavior. We have data for 21 experts located in as many countries who make SKU‐level forecasts for a variety of pharmaceutical products for October 2006 to September 2007. We study the behavior of the experts by comparing their forecasts with those from an automated statistical program, and we report the forecast accuracy over these 12 months. In September 2007 these experts were given feedback on their behavior and they received training at the headquarters office, where specific attention was given to the ins and outs of the statistical program. Next, we study the behavior of the experts for the 3 months after the training session, i.e. October 2007 to December 2007. Our main conclusion is that in the second period the experts’ forecasts deviated less from the statistical forecasts and that their accuracy improved substantially. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
18.
The aquaporin protein family generally seems to be designed for the selective passage of water or glycerol. Charged molecules,
metal ions and even protons are strictly excluded. Recently, particular aquaporin isoforms were reported to conduct unconventional
permeants, i.e., the unpolar gases carbon dioxide and nitric oxide, the polar gas ammonia, the oxidative oxygen species hydrogen peroxide,
and the metalloids antimonite, arsenite and silicic acid. Here, we summarize the available data on permeability properties
and physiological settings of these aquaporins and we analyze which structural features might be connected to permeability
for non-water, non-glycerol solutes.
Received 31 March 2007; received after revision 3 May 2007; accepted 23 May 2007 相似文献
19.
Roglio I Bianchi R Giatti S Cavaletti G Caruso D Scurati S Crippa D Garcia-Segura LM Camozzi F Lauria G Melcangi RC 《Cellular and molecular life sciences : CMLS》2007,64(9):1158-1168
In this study we have assessed the effect of testosterone (T), dihydrotestosterone (DHT) and 5αandrostan-3α, 17β-diol (3α-diol)
therapies on diabetic neuropathy. Diabetes was induced in adult male rats by the injection of streptozotocin and resulted
in decreased T and increased 3α-diol levels in plasma and in decreased levels of pregnenolone and DHT in the sciatic nerve.
Moreover, a reduced expression of the enzyme converting Tinto DHT (i.e., the 5α-reductase) also occurs at the level of sciatic nerve, suggesting that the decrease of DHT levels could be due to
an impairment of this enzyme. Chronic treatment for 1 month with DHT or 3α-diol increased tail nerve conduction velocity and
partially counteracted the increase of thermal threshold induced by diabetes. Treatment with DHT increased tibial Na+,K+-ATPase activity and the expression of myelin protein P0 in the sciatic nerve.DHT, 3α-diol and T reversed the reduction of
intra-epidermal nerve fiber density induced by diabetes. These observations indicate that T metabolites can reverse behavioral,
neurophysiological, morphological and biochemical alterations induced by peripheral diabetic neuropathy.
I. Roglio, R. Bianchi: These authors contributed equally to this study.
Received 4 January 2007; received after revision 13 February 2007; accepted 27 March 2007 相似文献
20.
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