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At least 307 records · Page 17Linked to original sources

PubMed2005

Plasmid vaccines and therapeutics: from design to applications.

In the late 1980s, Vical and collaborators discovered that the injection into tissues of unformulated plasmid encoding various proteins resulted in the uptake of the plasmid by cells and expression of the encoded proteins. After this discovery, a period of technological improvements in plasmid delivery and expression and in pharmaceutical and manufacturing development was quickly followed by a plethora of human clinical trials testing the ability of injected plasmid to provide therapeutic benefits. In this chapter, we summarize in detail the technologies used in the most recent company-sponsored clinical trials and discuss the potential for future improvements in plasmid design, manufacturing, delivery, formulation and administration. A generic path for the clinical development of plasmid-based products is outlined and then exemplified using a case study on the development of a plasmid vaccine from concept to clinical trial.

Anthrax Vaccines↗

PubMed2005

Genetic epidemiology of anxiety disorders.

This chapter reviews the genetic epidemiology of the major subtypes of anxiety disorders including panic disorder, phobic disorders, generalized anxiety disorder, and obsessive-compulsive disorder. Controlled family studies reveal that all of these anxiety subtypes are familial, and twin studies suggest that the familial aggregation is attributable in part to genetic factors. Panic disorder and, its spectrum have the strongest magnitude of familial clustering and genetic underpinnings. Studies of offspring of parents with anxiety disorders an increased risk of mood and anxiety disorders, but there is far less specificity of the manifestations of anxiety in children and young adolescents. Although there has been a plethora of studies designed to identify genes underlying these conditions, to date, no specific genetic loci have been identified and replicated in independent samples.

Adult↗

PubMed2006

Extraneuronal monoamine transporter and organic cation transporters 1 and 2: a review of transport efficiency.

The extraneuronal monoamine transporter (EMT) corresponds to the classical steroid-sensitive monoamine transport mechanism that was first described as "uptake2" in rat heart with noradrenaline as substrate. The organic cation transporters OCT1 and OCT2 are related to EMT. The three carriers share basic structural and functional characteristics. Hence, EMT, OCT1 and OCT2 constitute a group referred to as non-neuronal monoamine transporters or organic cation transporters. After a brief general introduction, this review focuses on the critical analysis of substrate specificity. We calculate from the available literature and compare consensus transport efficiency (clearance) data for human and rat EMT, OCT1 and OCT2, expressed in transfected cell lines. From the plethora of inhibitors that have been tested, the casual observer likely gets the impression that these carriers indiscriminately transport very many compounds. However, our knowledge about actual substrates is rather limited. 1-Methyl-4-phenylpyridinium (MPP+) is an excellent substrate for all three carriers, with clearances typically in the range of 20-50 microl min(-1) mg protein(-1). The second-best general substrate is tyramine with a transport efficiency (TE) range relative to MPP+ of 20%-70%. The TEs of OCT1 and OCT2 for dopamine, noradrenaline, adrenaline and 5-HT in general are rather low, in the range relative to MPP+ of 5%-15%. This suggests that OCT1 and OCT2 are not primarily dedicated to transport these monoamine transmitters; only EMT may play a significant role in catecholamine inactivation. For many substrates, such as tetraethylammonium, histamine, agmatine, guanidine, cimetidine, creatinine, choline and acetylcholine, the transport efficiencies are markedly different among the carriers.

1-Methyl-4-phenylpyridinium↗

PubMed2006

Neural crest stem cells.

Stem cells are defined by their ability to both self-renew and give rise to multiple lineages in vivo and/or in vitro. As discussed in other chapters in this volume, the embryonic neural crest is a multipotent tissue that gives rise to a plethora of differentiated cell types in the adult organism and is unique to vertebrate embryos. From the point of view of stem cell biology, the neural crest is an ideal source for multipotent adult stem cells. Significant advances have been made in the past few years isolating neural crest stem cell lines that can be maintained in vitro and can give rise to many neural crest derivatives either in vitro or when placed back into the context of an embryo. The initial work identifying these stem cells was carried out with premigratory neural crest from the embryonic neural tube. Later, neural crest stem cells were isolated from postmigratory neural crest, presumably more restricted in developmental potential. More recently it has been demonstrated that neural crest stem cell progenitors persist in the adult in at least two differentiated tissues, the enteric nervous system of the gut and the whisker follicles of the facial skin. In all cases, the properties of the stem cells derived reflect their tissue of origin and the potential of the progenitors becomes more restricted with age. In this chapter we will review this work and speculate on future possibilities with respect to combining our knowledge of neural crest gene function in the embryo and the manipulation of adult neural crest stem cells in vitro and eventually in vivo.

Animals↗

PubMed2002

Purines and neuroprotection.

The activation of adenosine A1, A2 andA3 receptors can protect neurones against damage generated by mechanical or hypoxic/ischaemic insults as well as excitotoxins. A1 receptors are probably effective by suppressing transmitter release and producing neuronal hyperpolarisation. They are less likely to be of therapeutic importance due to the plethora of side effects resulting from A1 agonism, although the existence of receptor subtypes and recent synthetic chemistry efforts to increase ligand selectivity, may yet yield clinically viable compounds. Activation of A2A receptors can protect neurons, although there is much uncertainty as to whether agonists are acting centrally or via a peripheral mechanism such as altering blood flow or immune cell function. Selective antagonists at the A2A receptor, such as 4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-yl-amino]ethyl)phenol (ZM 241385) and 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), can also protect against neuronal death produced by ischaemia or excitotoxicity. In addition, A2A receptor antagonists can reduce damage produced by combinations of subthreshold doses of the endogenous excitotoxin quinolinic acid and free radicals. Since the A2A receptors do not seem to be activated by normal endogenous levels of adenosine, their blockade should not generate significant side effects, so that A2A receptor antagonists appear to be promising candidates as new drugs for the prevention of neuronal damage. Adenosine A3 receptors have received less attention to date, but agonists are clearly able to afford protection against damage when administered chronically. Given the disappointing lack of success of NMDA receptor antagonists in human stroke patients, despite their early promise in animal models, it is possible that A2A receptor antagonists could have a far greater clinical utility.

Adenosine↗

PubMed1995

Cellular mechanisms involved in morphine-mediated suppression of CTL activity.

Based on a plethora of data from many laboratories, we have proposed the following mechanisms by which morphine alters immune homeostasis and immunocompetence in vivo (Fig. 2). Specifically, the administration of morphine subcutaneously via routing through blood interacts directly with opioid receptors on cells of the immune system or on receptors within the central nervous system. Although there is currently no evidence to support the direct involvement of morphine on lymphocyte opioid receptors, in vitro studies show the existence of functional, naloxone-sensitive opioid receptors (25). In addition, pharmacological and biochemical characterization of lymphocyte opioid receptors has been shown to be consistent in many instances, with the profile of neural-derived opioid receptors (25-27). Finally, recent molecular studies using oligonucleotide primers specific for the delta-class opioid receptor cloned from NG-108-15 cells (28) have been used in reverse transcription-polymerase chain reactions to generate a 400 bp product in SL which has 100% sequence homology with a published opioid receptor cloned from a brain library (35). However, future studies are necessary to establish the role of lymphocyte opioid receptors following the in vivo administration of opioids (e.g. fentanyl, methadone, and morphine). Since the administration of morphine subcutaneously appears to predominately interact with brain opioid receptors (3) located in the mesencephalon (5), other neuroendocrine systems become candidates for activation and subsequent direct modulation of immune function: (i) the HPA axis and (ii) the sympathetic nervous system (SNS).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation.

The copper binding tripeptide, glycyl-L-histidyl-L-lysine [GHK:Cu(II)] has a plethora of biological effects related to the wound healing process. The presence of iron complexes in damaged tissues is detrimental to wound healing, due to local inflammation, as well as microbial infection mediated by iron. To test if the wound healing properties of GHK:Cu(II) are due to an affect on iron metabolism, we examined the effects of GHK:Cu(II) on iron catalyzed lipid peroxidation. GHK:Cu(II) inhibited lipid peroxidation only if the iron source was ferritin. Whereas GHK:Cu(II) inhibited ferritin iron release it did not exhibit significant superoxide dismutase-like or ceruloplasmin-like activity. We propose that GHK:Cu(II) binds to the channels of ferritin involved in iron release and physically prevents the release of Fe(II). Thus, a biological effect of GHK:Cu(II), possibly related to wound healing, may be the inhibition of ferritin iron release in damaged tissues, preventing inflammation and microbial infections.

Animals↗

PubMed2004

Membrane/cytoskeleton communication.

Accumulations of particular lipids in ordered arrays in the membrane (termed microdomains or lipid rafts) can attract proteins with specific targeting domains. Both the lipid and protein components of rafts communicate with the cytoskeleton directly thereby regulating cellular responses. Recent evidence implicating phosphoinositide 1,5 bisphosphate (PIP2) in cytoskeletal regulation shows that agonist sensitive regulation of PIP2 homoeostasis occurs specifically rafts, which appear to provide a major structural substrate for its function. The crucial role of PIP2 in generating cytoskeletal responses is chiefly achieved by regulating proteins that control actin dynamics directly. Many of these regulatory proteins are also specifically enriched in rafts either directly (by insertion into the lipid bilayer via acetylation motifs), or indirectly via interactions with other raft components. The notion that rafts form membrane platforms or modules that mediate signaling responses has been most extensively demonstrated in the immune synapse (IS) of T cells, a complex assemblage of rafts that integrates signaling cascades originating from the simultaneous activation of a wide variety of receptors. The IS is essential for both the amplification and maintenance of T-cell activation, and its assembly at the antigen presenting site depends on the interactions between rafts and the actin cytoskeleton that regulates coalescence of smaller raft components into the larger IS complex. Likewise the neuron, which represents the most highly polarized cell in the body, utilizes the regulation of actin dynamics in response to a plethora of extracellular signals to control axon pathfinding thereby sculpting nervous system cytoarchitecture with utmost precision. It is now becoming clear, that as in the T-cell, lipid rafts in the growing axon can assemble into highly specific, yet malleable and dynamic, signaling modules that regulate actin dynamics in a fashion that is also PIP2-dependent and that utilizes both familiar and novel regulatory mechanisms. It seems clear that raft mediated cytoskeletal regulation represents a highly conserved mechanism to integrate cellular responses to diverse signals.

Actins↗

PubMed1994

Ethnic and genetic differences in susceptibility to osteoporotic fractures.

A plethora of investigations in recent years has demonstrated the occurrence of ethnic differences in bone mineral content, bone density and fracture rates. These findings indicate that genetic determinants exist both for bone development during growth and for bone loss during aging. Twin and parent-offspring studies have corroborated the existence of a hereditary component. It is most evident in the greater bone mass and lower fracture rate in blacks than in whites. Differences in bone mass between Asians and whites are less clear than between blacks and whites because of disparities in body size and other confounding factors. Black children and adults excrete less urinary calcium than whites on essentially the same diets and consequently retain more calcium in their skeletons. Better calcium retention is commensurate with the faster rate of bone growth of black children.

Adolescent↗

PubMed1987

Cognitive deficits related to memory impairments in alcoholism.

Cognitive impairments related to alcoholism are examined in terms of input, intervening, and output variables. Respectively, the dysfunctions are represented by visuospatial/perceptual abnormalities, affective/conative deficits, and strong perseverative response tendencies. Defects in one or more of these aspects of cognitive functioning may appear as problems of memory. Functional differences between subgroups of alcoholics who do and do not develop severe anterograde amnesia characteristic of Korsakoff's syndrome presumably are attributable to differences in the distribution and extent of brain pathology. Both subgroups have widespread cortical pathology, which may play an important role in stimulus-processing deficiencies observed in both. Korsakoff's have demonstrated a more significant degree of pathology in diencephalic and basal forebrain structures than that observed in non-Korsakoff alcoholics; this may contribute to the greater memory and affective impairments in the former. However, in no subgroup of alcoholics can a single functional system or brain region be implicated as the major contributory factor. Rather, damage to multiple brain regions likely is responsible for the plethora of cognitive difficulties reported in the alcoholism literature.

Alcohol Amnestic Disorder↗

PubMed2006

Laser scanning cytometry: principles and applications.

The laser scanning cytometer (LSC) is the microscope-based cytofluorometer that offers a plethora of analytical capabilities. Multilaser-excited fluorescence emitted from individual cells is measured at several wavelength ranges, rapidly (up to 5000 cells/min), with high sensitivity and accuracy. The following applications of LSC are reviewed: (1) identification of cells that differ in degree of chromatin condensation (e.g., mitotic or apoptotic cells or lymphocytes vs granulocytes vs monocytes); (2) detection of translocation between cytoplasm vs nucleus or nucleoplasm vs nucleolus of regulatory molecules such as NF-kappaB, p53, or Bax; (3) semiautomatic scoring of micronuclei in mutagenicity assays; (4) analysis of fluorescence in situ hybridization; (5) enumeration and morphometry of nucleoli; (6) analysis of phenotype of progeny of individual cells in clonogenicity assay; (7) cell immunophenotyping; (8) visual examination, imaging, or sequential analysis of the cells measured earlier upon their relocation, using different probes; (9) in situ enzyme kinetics and other time-resolved processes; (10) analysis of tissue section architecture; (11) application for hypocellular samples (needle aspirate, spinal fluid, etc.); (12) other clinical applications. Advantages and limitations of LSC are discussed and compared with flow cytometry.

Cell Nucleus↗

PubMed2007

Revealing the metabolome of animal tissues using 1H nuclear magnetic resonance spectroscopy.

The measurement of tissue-specific metabolic fingerprints can be of particular interest when investigating disease processes, mechanisms of toxicity, or when knowledge of the metabolic interactions between different organs is required. This chapter presents several optimized protocols for the extraction of metabolites from animal tissues, their analysis by 1H nuclear magnetic resonance (NMR) spectroscopy, and the subsequent spectral preprocessing required for an NMR-based metabolomics experiment. First, the three critical steps in the preparation of tissue extracts for NMR analysis are described, including both a perchloric acid protocol for the extraction of polar metabolites, and a methanol:chloroform protocol for extraction of polar and lipophilic metabolites. Then a series of NMR experiments are described including a standard one-dimensional (1D) 1H NMR study, a 1D 1H Carr-Purcell-Meiboom-Gill spin-echo experiment, and a two-dimensional 1H-1H J-resolved NMR experiment. The advantages and limitations of each experiment for metabolomics research are discussed. Analysis of the resulting NMR datasets is typically conducted in two phases comprising "low level" spectral preprocessing and "high level" multivariate analysis. NMR spectral preprocessing is a critical step that converts raw NMR spectra into an appropriate data format for multivariate analysis. A detailed protocol for preprocessing NMR data, using ProMetab software, is presented. Because a plethora of algorithms exist for multivariate analyses, which can be used to construct classification models or for biomarker discovery, this is beyond the scope of the current chapter.

Animals↗

PubMed2003

Crystallins, genes and cataract.

Far from being a physical entity, assembled of inanimate structural proteins, the ocular lens epitomizes the biological ingenuity that sustains an essential and near-perfect physical system of immaculate optics. Crystallins (alpha, beta, and gamma) provide transparency by dint of their high concentration, but it is debatable whether proteins that provide transparency are any different, biologically or structurally, from those that are present in non-transparent structures or tissues. It is becoming increasingly clear that crystallins may have a plethora of metabolic and regulatory functions, both within the lens as well as outside of it. Alpha-crystallins are members of a small heat shock family of proteins and beta/gamma-crystallins belong to the family of epidermis-specific differentiation proteins. Crystallin gene expression has been studied from the perspective of the lens specificity of their promoters. Mutations in alpha-, beta-, and gamma-crystallins are linked with the phenotype of the loss of transparency. Understanding catalytic, non-structural properties of crystallins may be critical for understanding the malfunction in molecular cascades that lead to cataractogenesis and its eventual therapeutic amelioration.

Animals↗

PubMed2000

Neuropeptides in drug research.

Neuropeptides have been a subject of considerable interest in the pharmaceutical industry over the last 20 years or more. Many drug discovery teams have contributed to our understanding of neuropeptide biology but no significant drugs that act selectively upon neuropeptide receptors have yet emerged from the clinic. There are, however, a plethora of clinically useful drugs that act at other classes of neurotransmitter and neuromodulator receptors, many of them discovered over the last 20 years. Nevertheless, we think that the future for the discovery of novel drugs acting at neuropeptide receptors looks bright for two reasons: (1) there has been a substantial increase in our understanding of the function of neuropeptides; and (2) high-throughput screening (HTS) against neuropeptide receptors has now begun to yield many interesting drug-like molecules, rather than peptides, that have the potential to become clinically useful drugs. The objective of this review is to summarise our current understanding of specific areas of neuropeptide biology and pharmacology in the CNS as well as the PNS. We will also speculate on where we think the new generation of neuropeptide agonists and antagonists could emerge from the clinic.

Animals↗

PubMed2000

Vaccines and infectious disease.

The exponential growth in vaccine research over the last decade, in which many infectious diseases now appear to be amenable to prevention through immunization, is built upon three factors: first, a richer understanding of the immune response (in particular, cellular immunity), second, a greater finesse in understanding the molecular biology of pathogenicity, and third, an expanding use of genetic engineering techniques either to create micro-organisms of greatly attenuated virulence that may be used as vaccines, or to sequence, and express, potential vaccine antigens. With respect to vaccines composed of purified antigens, parallel work is underway to develop immuno-modulating agents (adjuvants) that will selectively and safely induce the necessary immune response. Finally, within this plethora of vaccine candidates, vaccinologists are devoting much effort to alternatives to immunization via injection, such as administration of a vaccine through the mucosal route (e.g., oral, intranasal, intravaginal, etc.), through the transcutaneous route, and even by expression of vaccine antigens in edible fruits and vegetables.

Clinical Trials as Topic↗

PubMed2007

Know thy neighbor: a survey of diseases and complex syndromes that map to chromosomal regions encoding TRP channels.

On the basis of their ever-expanding roles, not only in sensory signaling but also in a plethora of other, often Ca(2+)-mediated actions in cell and whole body homeostasis, it is suggested that mutations in TRP channel genes not only cause disease states but also contribute in more subtle ways to simple and complex diseases. A survey is therefore presented of diseases and syndromes that map to one or multiple chromosomal loci containing TRP channel genes. A visual map of the chromosomal locations of TRP channel genes in man and mouse is also presented.

Animals↗

PubMed2001

Cellular receptors and hantavirus pathogenesis.

Hantaviruses cause two potentially lethal diseases, HPS and HFRS, and both diseases result in defects in vascular permeability and platelet function. Human beta 3 integrins confer cellular susceptibility to HPS- and HFRS-causing hantaviruses, a fact directly linking platelets, endothelial cells, and hantavirus diseases to the use of [figure: see text] cellular receptors that maintain capillary integrity and regulate platelet function. The role of vitronectin, PAI-1, uPAR, and complement cascades in hantavirus pathogenesis are unstudied but may contribute to specific disease syndromes effected by hantaviruses. The divergence of hantavirus surface glycoproteins and common beta 3-integrin usage provides further insight into the interaction of hantaviruses with cells. G1 and G2 glycoprotein variation is likely to contribute to additional interactions that determine pathogenic responses to individual viruses. beta 3-integrin usage also suggests that common elements exist on G1 or the more highly conserved G2 surface glycoprotein, which mediate viral attachment to integrins. Although there is currently no data defining the virion attachment protein, the development of antibodies that recognize the hantavirus attachment protein and block integrin interactions is of interest since it is likely to provide an additional point for therapeutic intervention and vaccine development. There are a plethora of effects that could be elicited by hantavirus regulation of cellular beta 3 integrins and their ligands that are consistent with hantavirus diseases. Since beta 3 integrins are critical adhesive receptors on platelets and endothelial cells and regulate both vascular permeability and platelet activation and adhesion, the use of these receptors by hantaviruses is likely to be fundamental to hantavirus pathogenesis. The lack of an animal model for hantavirus pathogenesis has prevented a systematic analysis of immune and cellular responses to hantavirus infections, and it impedes our ability to study protective or therapeutic approaches to hantavirus diseases. However, recent findings suggest that human beta 3 integrins within transgenic mice may provide animal models of hantavirus pathogenesis and have the potential to radically alter the ability to investigate hantavirus disease.

Animals↗

PubMed2002

Cytosolic glucocorticoid receptor-interacting proteins.

Studies of GR-interacting proteins can provide valuable insights into the regulation of GR cellular signalling. The cytoplasmic localization of GR and reports of GR interaction with such a plethora of other cytoplasmic proteins may point to a unique role for GR in modulating and integrating other signalling pathways. A better insight into these interactions could serve as a tool when trying to understand and modify GR signalling.

14-3-3 Proteins↗