Showing papers in "Handbook of experimental pharmacology in 1999"
Journal Article•
125 citations
TL;DR: All retinoids (vitamin A and its analogs) in the body originate in the diet either as preformed vitamin A, usually from animal food sources, or as provitamin A carotenoids,usually from plant food sources or as supplements or additives to processed foods.
Abstract: All retinoids (vitamin A and its analogs) in the body originate in the diet either as preformed vitamin A, usually from animal food sources, or as provitamin A carotenoids, usually from plant food sources or as supplements or additives to processed foods. Both preformed vitamin A and provitamin A undergo metabolism within the intestine (Blaner and Olson 1994), including a series of metabolic conversions, extracellularly in the lumen of the intestine and intracellularly in the intestinal mucosa, which result in the preponderance of the dietary vitamin A being converted to retinol (vitamin A alcohol). The retinol, along with other dietary lipids in the intestinal mucosa, is packaged as retinyl ester in nascent chylomicrons. The chylomicrons are secreted into the lymphatic system, and approximately 75% of chylomicron retinoid is eventually taken up as part of the chylomicron remnants by the liver, where the majority of the body’s retinoid reserves are stored. Some retinoid is delivered to extrahepatic tissues where this retinoid is either stored as retinyl ester, released back into the circulation for delivery to the liver and other tissues, metabolized to active retinoid forms such as retinoic acid or metabolized to catabolic forms destined for excretion from the body.
89 citations
TL;DR: In epilepsy research, animal models are used to evaluate the possible specific efficacies of the compound against different types of seizures or epilepsy, and to characterize the preclinical efficacy of novel compounds during chronic administration.
Abstract: In epilepsy research, animal models serve a variety of purposes. First, they are used in the search for new antiepileptic drugs. Second, once the anticonvulsant activity of a novel compound has been detected, animal models are used to evaluate the possible specific efficacies of the compound against different types of seizures or epilepsy. Third, animal models can be used to characterize the preclinical efficacy of novel compounds during chronic administration. Such chronic studies can serve different objectives, for instance, evaluation of whether drug efficacy changes during prolonged treatment, e.g. because of the development of tolerance, or examination of whether a drug exerts antiepilep-togenic effects during prolonged administration, i.e. is a true antiepileptic drug. Fourth, animal models are employed to characterize the mechanism of action of old and new antiepileptic drugs. Fifth, certain models can be used to study mechanisms of drug resistance in epilepsy. Sixth, in view of the possibility that chronic brain dysfunction, such as epilepsy, might lead to altered sensitivity to drug adverse effects, models involving epileptic animals are useful to study whether epileptogenesis alters the adverse effect potential of a given drug. Seventh, animal models are needed for studies on the pathophysiology of epilepsies and epileptic seizures, e.g. the processes involved in epileptogenesis and ictogenesis (Lothman 1996a).
78 citations
TL;DR: By 1987, all of the major ligand-gated ion-channel families had succumbed to cloning efforts, with one notable exception, the glutamate receptors, and the glycine receptor cDNA had been isolated in 1987 by taking advantage of the specific high-affinity binding of the competitive antagonist strychnine to the receptor.
Abstract: By 1987, all of the major ligand-gated ion-channel families had succumbed to cloning efforts, with one notable exception, the glutamate receptors. Acetylcholine receptors had been cloned first, aided by the fact that these proteins bind α-bungarotoxin with high specificity and affinity, and that they are highly concentrated in the muscle tissue of the electric fish Torpedo californica and Torpedo marmorata. This had allowed protein purification followed by partial microsequencing (Devillers-Thiery et al. 1979; Raftery et al. 1980) as well as generation of antibodies (Tzartos and Lindstrom 1980). The resulting information and analytical tools, in turn, had been used to screen cDNA libraries with amino acid sequence-derived oligonucleotide probes and antibodies which, in 1982, had led to the isolation of the first cDNA clones for acetylcholine receptors (BALLIVET et al. 1982; Giraudat et al. 1982; Noda et al. 1982; Sumikawa et al. 1982). A glycine receptor cDNA had been isolated in 1987 by taking advantage of the specific high-affinity binding of the competitive antagonist strychnine to the receptor. This allowed isolation and partial microsequencing of a strychnine-binding protein (Pfeiffer et al. 1982), providing sequence information to construct specific oligonucleotide probes, which were then used to isolate the glycine receptor cDNA (Grenningloh et al. 1987). γ-Aminobutyric acid (GABA)A receptors were also cloned in 1987, via low-stringency hybridization screening based on oligonucleotide sequence derived from the partial amino acid sequence of a protein purified by benzodiazepine-affinity chromatography (Schofield et al. 1987).
58 citations
TL;DR: This chapter chooses to highlight only selected topics on the expression, function and regulation of the 70-kDa heat shock protein, hsp70, and focuses primarily on studies with mammalian cells.
Abstract: One of the most interesting aspects of thermal biology in the mammalian system is the response of heated cells to subsequent heat challenges. When exposed to a mild, non-lethal heat shock, mammalian cells develop a transient resistance to subsequent thermal stress (thermotolerance). On the molecular level, heat shock activates a specific set of genes, so-called heat shock genes, and results in the preferential synthesis of heat shock proteins (hsps). The heat shock response was originally described as a phenomenon of inducible gene expression, and has rapidly become an extensively studied adaptive response to a diverse array of environmental stress. Heat shock and stress response was ubiquitous, and the genes encoding these heat shock proteins (or stress proteins) were highly conserved at the level of nucleotide sequences. The field of stress protein research, in the last decade, has attracted the attention of a wide spectrum of investigators, ranging from molecular and cell biologists to medical oncologists. Studies on stress proteins now include topics in molecular biology on gene expression via the complex signal transduction pathways that control the regulation of stress genes, in cell biology on the role of stress proteins as molecular chaperones that regulate various aspects of protein folding and transport, and in pathophysiology and medicine on the role of the stress proteins in human disease, as well as in immunobiology and infectious diseases on the involvement of these proteins in the immune response during tissue damage and infection. In this chapter, we have chosen, of necessity, to highlight only selected topics on the expression, function and regulation of the 70-kDa heat shock protein, hsp70. In addition, we focus primarily on studies with mammalian cells.
50 citations
TL;DR: Recent advances in immunology have provided insights into the specific, anti-infective protection and have thereby supplied the tools for selective stimulation of appropriate immune responses K(AUFMANN 1996a).
Abstract: Vaccinology can be viewed as an application of immunology. The two disciplines arose from a common root in the late nineteenth century, namely investigations of the host response to infectious agents. Emil von Behring, in studying the humoral immune response to the toxin-producing pathogens Clostridium tetani and Corynebacterium diphtheriae, realized the implication of his observation that protection can be transferred with sera from immunized animals (VON BEHRING 1915). In developing the therapeutic strategy of passive vaccination he relied on antibody quantifications developed by Paul Ehrlich (1904). Soon, however, vaccinology and immunology diverged. The vaccines in current use were often developed empirically and virtually independently of the progress made in basic immunology. This approach has now reached its limits. Novel vaccine generations are required for infectious diseases that still cause enormous health problems, and for which vaccines are not yet available. These vaccines can be developed only in the realm of modern immunology. Recent advances in immunology have provided insights into the specific, anti-infective protection and have thereby supplied the tools for selective stimulation of appropriate immune responses K(AUFMANN 1996a).
47 citations
TL;DR: Fat-soluble small molecule hormones and vitamins have long attracted the curiosity of molecular biologists, since they appeared to regulate gene expression in eukaryotic cells via similar mechanisms as certain signal molecules that had been studied extensively in prokaryotic systems.
Abstract: Fat-soluble small molecule hormones and vitamins have long attracted the curiosity of molecular biologists, since they appeared to regulate gene expression in eukaryotic cells via similar mechanisms as certain signal molecules that had been studied extensively in prokaryotic systems. Vitamin A and its natural and synthetic analogues and derivatives (the retinoids) were of particular interest because of a variety of reasons. Starting a century ago it became more and more obvious that vitamin A played a very central role in the regulation and timing of many important biological processes, including development, differentiation, morphogenesis, growth, metabolism and homeostasis. Because of their central biological roles it appeared possible that retinoids serve as therapeutic agents, increasing the desire and need to understand their molecular mechanism of action. This became particularly important when synthetic vitamin A derivatives were sought with fewer undesirable side effects. Thus not surprisingly, as soon as the molecular biology technologies became available, a rapid progress was made in the deciphering of molecular signal trans- duction pathways of small fat soluble hormones and vitamins including the retinoids.
41 citations
TL;DR: Attention focuses on how an understanding of the retinoid signaling pathway provides insight into mechanisms responsible for retinoids clinical responses, and how this convergence through an analysis ofretinoid-based cancer therapy and prevention mechanisms is discussed.
Abstract: The retinoids, synthetic and natural derivatives of vitamin A, are ligands activating nuclear transcription factors that are members of the steroid receptor superfamily. Ligand-retinoid receptor interactions lead to activation or repression of target genes which in turn signal retinoid biological actions. There is a convergence of basic scientific and clinical findings in the retinoid field. As a fuller understanding of the retinoid signaling pathway has evolved, beneficial clinical effects were found using the retinoids in cancer therapy and prevention. Underscoring this convergence is the tight link that often exists between observed clinical retinoid responses and activation or repression of specific retinoid receptors. This chapter discusses this convergence through an analysis of retinoid-based cancer therapy and prevention mechanisms. Attention focuses on how an understanding of the retinoid signaling pathway provides insight into mechanisms responsible for retinoid clinical responses.
33 citations
TL;DR: Small heat shock proteins, now denoted small stress proteins (sHsp), are characterized by a domain of homology to aA,B-crystallin proteins from vertebrate eye and are less conserved than the large Hsp (i.e., Hsp70) since, among species, they show greater variations in sequence, in number and in molecular mass.
Abstract: Investigations of the cellular response to thermal and other types of stresses have allowed the identification of families of proteins (the heat shock or stress proteins, Hsp) whose expression is enhanced when environmental conditions become deleterious (reviewed in Georgopoulos and Welch 1993; Morimoto et al. 1994). Hsp are subdivided in two groups, based on their apparent molecular mass, i.e., the large and small heat shock proteins. Small heat shock proteins, now denoted small stress proteins (sHsp), are characterized by a domain of homology to aA,B-crystallin proteins from vertebrate eye (reviewed in Arrigo and Landry 1994). Despite this particular homology, sHsp are less conserved than the large Hsp (i.e., Hsp70) since, among species, they show greater variations in sequence, in number and in molecular mass. All sHsp analyzed so far share the extreme tendency to form oligomers. Like a-crystallin, sHsp are in the form of aggregates with heterodispersed native molecular masses (which can reach up to 800 kDa or more). This structural organization of sHsp depends on the physiology of the cell and probably also on the phosphorylation of these proteins (Siezen et al. 1978a; Arrigo 1987; Arrigo and Welch 1987; Arrigo et al. 1988; Kato et al. 1994; Lavoie et al. 1995; Mehlen and Arrigo 1994; Mehlen et al. 1995b,c).
31 citations
TL;DR: As the cellular mechanisms underlying the various forms of human motoneuron disease (MND) are still incompletely understood, the embryonic form of motoneurons loss serves as an important model for these diseases.
Abstract: In higher vertebrates, motoneurons are generated in excess during embryonic development, and a significant proportion of the newly generated cells that have already, at that time, made functional contact with their target field, the skeletal muscle, are eliminated. In 6-day-old chick embryos, the lumbar part of the spinal cord contains about 20000 motoneurons, of which about 8000 are lost until embryonic day 12 (see Oppenheim 1991 for review). This loss of motoneurons has been named “physiological cell death” in contrast to “pathological cell death” which is characteristic of various forms of motoneuron disease. Such diseases lead to paresis of the musculature and finally result in death, in most cases, as a consequence of respiratory failure (see Smith 1992, for review). As the cellular mechanisms underlying the various forms of human motoneuron disease (MND) are still incompletely understood, the embryonic form of motoneuron loss serves as an important model for these diseases.
31 citations
TL;DR: The vertebrate visual process is remarkable in its properties, allowing detection of contrast over an approx.
Abstract: The vertebrate visual process is remarkable in its properties. Visual pigments characterized from various species vary in their maximum wavelength sensitivity from 380 nm to 620 nm, yet each has the same chromophore, 11-cis-retinal (or its 3-dehydro- or 3-hydroxy-derivative), which absorbs at 383 nm (393 nm, 3-dehydroretinal). The dynamic range of the visual system is enormous, allowing detection of contrast over an approx. 1010-fold range of background intensities. This is accomplished, in part, by employing highly sensitive rod photoreceptors at low levels of illumination and less sensitive cone photoreceptors at higher levels of illumination. In addition, photoreceptors are capable of reducing their sensitivity in response to increasing background illumination (adaptation), contributing to the dynamic range of the visual system. The extreme sensitivity of the visual system to photostimulation requires a low background of dark noise, a condition met by enveloping the chromophore within the interior of a protein (opsin) to form a structure with an isomerization activation barrier of 45kcallmole (Birge 1990), ensuring that thermal isomerization of rhodopsin is a rare event (but see Barlow et al. 1993). The resulting t ½ of the complex for thermal excitation is 420 years (Baylor et al. 1984). Some of the sensitivity of rod photoreceptors results from their participation in summation pools, in which the output from hundreds of rods converges on one downstream neuron (a ganglion cell).
TL;DR: Although primarily cytoplasmic in unstressed cells, HSp90 rapidly accumulates in cell nuclei following various stresses including heat shock, and recent studies have shown that Hsp90 participates in multiple signal transduction pathways.
Abstract: Heat shock protein 90 (Hsp90) is one of the most abundant proteins in eukaryotic cells, comprising 1-2% of total cellular protein even under non-stress conditions. Hsp90 is highly evolutionarily conserved, with homologs in such divergent species as bacteria, yeast, Drosophila and humans (for review, see Pratt and Toft 1997). Mutational analysis in yeast has demonstrated an absolute Hsp90 requirement for cell survival (Parsell and Lindquist 1993) (although it is not essential in prokaryotes), and recent studies have shown that Hsp90 participates in multiple signal transduction pathways. The development of early eukaryotic cells from prokaryotic progenitors appears to have been accompanied by gene duplication of both Hsp70 and Hsp90 (Gupta and Golding 1996). In mammalian cells, there are two Hsp90 isomers in the cytosol (Hsp90a and Hsp9Os in humans (Hickey et al. 1989), Hsp86 and Hsp84 in mice (Perdew et al. 1993)), while a third homolog, glucose regulated protein 94 (Grp94), is localized primarily to the endoplasmic reticulum (Little et al. 1994; Wearsch and Nicchitta 1996). Two recent reports have identified an additional, truncated, cytosolic member of the family, designated Hsp75 (Chen et al. 1996a; Song et al. 1995). Hsp90 exists as a dimer, and while homodimers appear to be more common (Minami et al. 1991, 1994), heterodimerization of Hsp90a and Hsp9Os can occur (Perdew et al. 1993). Although primarily cytoplasmic in unstressed cells, Hsp90 rapidly accumulates in cell nuclei following various stresses including heat shock (Akner et al. 1992; Gasc et al. 1990).
TL;DR: It has long been understood that retinoic acid synthesis from its precursor retinol involves a two step oxidation that resembles the oxidation of ethanol to acetic acid.
Abstract: It is well known from the early literature that liver alcohol dehydrogenase catalyzes the oxidation of retinol to retinal (Blaner and Olson 1994). Similarly, it was established from early work that several members of the aldehyde dehydrogenase family of enzymes are able to catalyze irreversibly the oxidation of retinal to retinoic acid (Blaner and Olson 1994). Thus,it has long been understood that retinoic acid synthesis from its precursor retinol involves a two step oxidation that resembles the oxidation of ethanol to acetic acid.
TL;DR: The heat shock response is physiologi cally relevant since heat shock genes are turned on in the mammalian nervous system following stress treatments such as fever-like temperature, focal cerebral ischemia and subarachnoid hemorrhage and the type of brain cell that activates the heatshock response in vivo depends on the nature and the severity of the stress.
Abstract: Considerable advances in the molecular biology of the heat shock response and the role of heat shock proteins (hsps) in repair and protective mechanisms have been made using mammalian cells grown in tissue culture (Morimoto 1993; Morimoto et al. 1994; see also Chap. 3, this volume). Recently, an increasing amount of work has been carried out on intact thermoregulating animals. As will be shown in this article, the heat shock response is physiologi cally relevant since heat shock genes are turned on in the mammalian nervous system following stress treatments such as fever-like temperature, focal cerebral ischemia and subarachnoid hemorrhage. The brain is a complex structure composed of many cell types. As will become apparent, neuronal and glial cell types exhibit differences in constitutive expression of hsps and the type of brain cell that activates the heat shock response in vivo depends on the nature and the severity of the stress.
TL;DR: The elegant studies of JENSEN and his collaborators (1982) demonstrated that estrogen action was mediated by the estrogen receptor (ER), and the attenuation of activity in this signal pathway led to estrogen deprivation and growth inhibition, thus explaining the therapeutic effects that BEATSON reported following ovariectomy.
Abstract: Since 1896, when Sir George Beatson demonstrated that ovariectomy caused regression of mammary tumours in women, the key aim of endocrine breast cancer therapy has been to deprive the body of estrogen (BEATSON 1896). Ovariectomy accomplishes this by removing the gland that is the predominant source of estrogens in pre-menopausal women. Thus, estrogen deprivation is an effective therapy for breast cancer. It was only over half a century later that the mechanism of this therapy began to be explained. The elegant studies of JENSEN and his collaborators (1982) demonstrated that estrogen action was mediated by the estrogen receptor (ER). Binding of estrogen to ERs stimulated growth, and the attenuation of activity in this signal pathway led to estrogen deprivation and growth inhibition, thus explaining the therapeutic effects that BEATSON reported following ovariectomy. The knowledge generated through the years following Jensen’s first report on the ER can be visualised in Fig. 1.
TL;DR: Four distinct neurotrophin genes have been identified in mice and in humans that encode for small dimeric, secretory proteins named nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotphin-3 (NT3) and neurotroph in-4/5 (NT4/ 5).
Abstract: Neurotrophins are proteins that are structurally related and exert profound effects on cells of the nervous system. Four distinct neurotrophin genes have been identified in mice and in humans that encode for small dimeric, secretory proteins named nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5).
TL;DR: The evidence for a crucial role for vitamin A and its derivatives, the retinoids, in the development and maintenance of the nervous system is now beyond doubt, and this chapter presents the data to support this contention.
Abstract: The evidence for a crucial role for vitamin A and its derivatives, the retinoids, in the development and maintenance of the nervous system is now beyond doubt, and this chapter presents the data to support this contention. The evidence comes from several types of experiment: the induction of neural differentiation in embryonal carcinoma cells; the effects of excess retinoids; the effects of a deficiency of retinoids; the distribution of retinoid-binding proteins and retinoid receptors and the results of interference with their signalling functions; the detection of endogenous retinoids; and the distribution of retinoid synthesising enzymes. Each of these topics are reviewed below.
TL;DR: Interneurons forming inhibitory synapses on the somata or axon initial segments of their postsynaptic target cells are thought to set the threshold of action potential initiation and regulate plasticity at glutamatergic synapses in the cortex.
Abstract: Principal neurons and interneurons are the two main classes of cells in cortical neuronal networks. Principal neurons (granule cells or pyramidal neurons) have transregional axonal projections and release glutamate onto their postsynaptic target cells. In contrast, interneurons have local, but often extensive, axonal arborizations and use γ-aminobutyric acid (GABA) as a transmitter. Although interneurons represent only approximately 10% of the neuronal population, they control the electrical activity of the entire network (Freund and Buzsaki 1996). Interneurons forming inhibitory synapses on the somata or axon initial segments of their postsynaptic target cells are thought to set the threshold of action potential initiation (Miles et al. 1996) and can synchronize the collective activities of large principal neuron ensembles (Cobb et al. 1995). In contrast, interneurons establishing inhibitory synapses mainly on dendrites could suppress dendritic Na+ or Ca2+ spikes (Buzsaki et al. 1996; Miles et al. 1996) and, thus, regulate plasticity at glutamatergic synapses in the cortex (Davies et al. 1991).
TL;DR: The ability of all-trans-retinoic acid (ATRA) to induce differentiation of acute promyelocytic leukemia cells into granulocytes is the basis for its therapeutic activity in patients and ATRA is currently used for therapy of this type of cancer.
Abstract: Retinoids are a group of structural and functional analogs of vitamin A. They regulate a number of fundamental physiological processes including vision, reproduction, metabolism, differentiation, bone development, and pattern formation during embryogenesis (De Luca 1991; Gudas et al. 1994; Lotan 1995a). Certain retinoids are capable of modulating cell growth, differentiation, and apoptosis and suppressing carcinogenesis in a variety of tissue types (e.g., lung, skin, mammary gland, prostate, bladder) in animal models (Moon et al. 1994; Lotan 1996) and in clinical trials with patients with premalignant or malignant lesions of the oral cavity, cervix, bronchial epithelium, skin, and other organs (Kraemer et al. 1992; Hong and Itri 1994; Lotan 1996; Hong and Sporn 1997; Moon et al. 1997). Some retinoids exhibit antitumor activity against fully malignant cells in vitro as reflected by suppression of proliferation and induction of differentiation or apoptosis (Amos and Lotan 1991; Lotan et al. 1991; Gudas et al. 1994; Lotan 1995a). Consequently, retinoids are considered as potential therapeutic agents as well (Smith et al. 1992). The ability of all-trans-retinoic acid (ATRA) to induce differentiation of acute promyelocytic leukemia cells into granulocytes is the basis for its therapeutic activity in patients and ATRA is currently used for therapy of this type of cancer (Degos 1997; Suooignet et al. 1997; Tallman et al. 1997; see Chap. 11, Sect. III).
TL;DR: The transforming growth factor-β (TGF-β) superfamily harbors a number of examples to illustrate how growth factors with long-established functions in growth and differentiation control have unveiled astonishing capacities in regulating the survival and differentiation of neurons.
Abstract: Neurotrophic factors constitute signals of intercellular communication and are widely employed in signaling from neuronal target cells, neurons and glia towards responsive neurons. Although their prime function is apparently to rescue neurons from death, the past decade of neurotrophic-factor research has taught us that there is probably no such thing as a neurotrophic factor. Even the classic paradigmatic neurotrophic factor, nerve growth factor (NGF), may be beneficial to neurons (Levi-Montalcini 1987), disguise itself as a neuron killer (Frade et al. 1996) or perform multiple functions on non-neural cells which seem to be unrelated to its neurotrophic potential (Ehrhard et al. 1993). Similarly, growth factors with long-established functions in growth and differentiation control have unveiled astonishing capacities in regulating the survival and differentiation of neurons. The transforming growth factor-β (TGF-β) superfamily harbors a number of examples to illustrate this point.
TL;DR: Early observations serve as the foundation for the idea that all epithelial tissues, including the epidermis, require adequate vitamin A nutritional status to sustain normal growth and differentiation.
Abstract: Vitamin A, or retinol, has long been known to play a critical role in epithelial homeostasis. Its importance in the maintenance of healthy epithelium was first recognized by Mori (1922) with the discovery that the cornea became keratinized in vitamin A deficient animals. Soon thereafter Wolbach and Howe (1925) documented the conversion of mucosal epithelial tissues to squamous, metaplastic, hyperkeratinized epithelia — epithelia resembling the epidermis — in vitamin A deficient rats. In the authors’ words,“… replacement of many different epithelia by stratified keratinizing epithelium actually characterize[s] fat-soluble A avitaminosis. The specific pathology is the widespread keratinization.” Indeed, even normal or orthokeratotic skin appeared to require vitamin A, as Frazier and Hu (1931) and Goodwin (1934) later described the cutaneous hyperkeratosis that accompanies vitamin A deficiency in human beings. In addition, the hyperkeratosis observed in vitamin A deficiency could be reversed by restoring vitamin A to the diet (Frazier and Hu 1931; Goodwin 1934). These early observations serve as the foundation for the idea that all epithelial tissues, including the epidermis, require adequate vitamin A nutritional status to sustain normal growth and differentiation.
TL;DR: This chapter considers how the physical-chemical properties of retinoids and the characteristics of their interactions with the various environments in which they are distributed in vivo affect their biological functions.
Abstract: This chapter considers how the physical-chemical properties of retinoids and the characteristics of their interactions with the various environments in which they are distributed in vivo affect their biological functions. The discussion focuses on current knowledge on the equilibrium and kinetic parameters that govern the behavior of retinoids within aqueous phases, biological membranes, and binding sites of proteins. The possible implications of this information for the molecular mechanisms underlying some aspects of retinoid biology are then considered.
TL;DR: The importance of the micronutrient vitamin A throughout the life cycle has been well established in numerous studies, with its absolute essentialness being best illustrated in the avian embryo model.
Abstract: The importance of the micronutrient vitamin A throughout the life cycle has been well established in numerous studies (Moore 1957; Wolf 1984). It has more recently become quite clear that the requirement for vitamin A begins with embryonic life, and that retinoids, the vitamin A active forms that exert vitamin A function via their nuclear receptor, are critical signaling molecules during development, their absolute essentialness being best illustrated in the avian embryo model: vitamin A deficiency is embryolethal (DErsch and Zile 1993; Thompson 1969).
TL;DR: The study of the metabolism of estradiol began many years ago; it was primarily the chemical structures of the various breakdown products that were closely described.
Abstract: The study of the metabolism of estradiol began many years ago; it was primarily the chemical structures of the various breakdown products that were closely described. Only later was the effort made to research further into the enzyme systems required for that breakdown and, recently, into the receptors to which the metabolites bind in the tissues.
TL;DR: The variability in combinations and expression levels of receptors suggests that the properties of the physiological responses to glutamate, which are dependent on the composition of receptors, differ from neuron- to-neuron and synapse-to-synapse.
Abstract: The general distribution of ionotropic glutamate receptors has been described in numerous reviews (Hollmann and Heinemann 1994; Petralia and Wenthold 1996; Bahn and Wisden 1997; Petralia 1997; Watanabe 1997) and will be mentioned only briefly here. Glutamate receptors are found in nearly all neurons and in many types of glia in the central nervous system (CNS), as well as in many cells in the peripheral nervous system and in other structures. Each ionotropic glutamate receptor subunit shows a distinct pattern of distribution in the CNS. Some, such as the a-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) receptor subunits, G1uR2 and G1uR3, and the N-methyl-Daspartate (NMDA) receptor subunit NR1 are both abundant and widespread. Others, such as the AMPA receptor subunits, G1uR1 and GluR4, the NMDA receptor subunit NR2B, and the kainate receptor subunits, GluR5 and G1uR6, have a restricted distribution and are abundant in some areas of the brain and populations of neurons. For example, G1uR1 receptor subunits are abundant in most neurons of the hippocampus while they are rare in neurons of the cerebellum (although abundant in Bergmann glia; Fig. 1). Some glutamate receptor subunits, such as NR2 C and 82 which are expressed in cerebellar granule cells and Purkinje cells, respectively, are abundant only in one or a few structures. Finally, some ionotropic glutamate receptor subunits, such as the kainate receptor subunit, KA1, and 51, are expressed only at low levels. While the relative expression levels vary, most neurons express multiple subtypes and subunits of glutamate receptors. The variability in combinations and expression levels of receptors suggests that the properties of the physiological responses to glutamate, which are dependent on the composition of receptors, differ from neuron-to-neuron and synapse-to-synapse. For example, the virtual absence of GluR2 in AMPA receptors of most interneurons of the hippocampus and cerebral cortex indicates that these neurons express calcium-permeable AMPA receptors.
TL;DR: Two of the major molecular chaperones in eukaryotic organisms with essential functions in both stressed and non-stressed cells, which by binding and stabilizing unstable conformations of substrate proteins allow diverse proteins to fold correctly, assemble into oligomeric complexes or be transported across membranes in a partially unfolded state, act very differently.
Abstract: The 60-kDa heat shock protein (hsp60) and mitochondrial hsp70 (mhsp70) constitute two of the major molecular chaperones in eukaryotic organisms with essential functions in both stressed and non-stressed cells, which by binding and stabilizing unstable conformations of substrate proteins allow diverse proteins either to fold correctly, assemble into oligomeric complexes or be transported across membranes in a partially unfolded state (Ellis and van der Vies 1991; Craig et al. 1993; Ellis and Hartl 1996; Hartl 1996). They act very differently, however, and usually not in isolation from each other. Hsp60, also referred to as a chaperonin (Ellis and van der Vies 1991), has been regarded to be present and to function in protein folding only within organelles such as mitochondria and chloroplasts, which are of endosymbiotic origin, while the TCP-1 protein, which is only weakly sequence related to hsp60 (Gupta 1990a), functions as a chaperonin in the cytosolic compartment (Craig et al. 1993; Hartl 1996). In the case of hsp70, different hsp70 homologs encoded by separate nuclear genes are found in the cytosol, endoplasmic reticulum, mitochondria and chloroplasts. Of these, the mitochondrial hsp70 homolog is the most closely related to DnaK from gram negative bacteria, reflecting the endosymbiotic origin of this organelle (Gupta and Golding 1993).
TL;DR: It has been known for many years that vitamin A is required by the testis for spermatogenesis to occur and by the epididymis for the maturation of spermatozoa to occur, and dietary retinol is clearly required.
Abstract: It has been known for many years that vitamin A is required by the testis for spermatogenesis to occur and by the epididymis for the maturation of spermatozoa (Wolbach and Howe 1925; Howell et al. 1963; reviewed in Eskild and Hansson 1994). Animals maintained on a vitamin A deficient diet which has been supplemented with retinoic acid are relieved of virtually all the symptoms of vitamin A deficiency, except that they are blind and sterile (e.g., Howell et al. 1963). Although genetic studies would indicate that retinoic acid, not retinol, is the active retinoid functioning in spermatogenesis (Kastner et al. 1995), dietary retinol is clearly required. This requirement for dietary retinol, not retinoic acid, for the maintenance of spermatogenesis is likely due to the existence of the blood-testis barrier preventing retinol from being available to the adluminal part of the tubule. This barrier is perhaps more accurately referred to as the Sertoli cell barrier, since it is the specialized junctions in the Sertoli cells that sequester the meiotic and postmeiotic compartment from the circulation.
TL;DR: A variety of experimental models of thrombosis have been developed and utilized to elucidate the etiology and pathogenesis of thROMbosis and to search for effective antithrombotic agents.
Abstract: Under certain pathological conditions, thrombosis occurs in the arterial or venous system and may cause myocardial infarction, cerebral infarction, transient ischemic attack, or deep vein thrombosis (DVT). These thrombotic diseases are most common in the Western industrialized countries and affect millions of people every year (HIRSH and HOAK 1996). Over the last several decades, a variety of experimental models of thrombosis have been developed and utilized to elucidate the etiology and pathogenesis of thrombosis and to search for effective antithrombotic agents.
TL;DR: Estrogens and men - this is a topic which has been neglected for quite some time and it is only relatively recently that discussion of it has intensified remarkably.
Abstract: Estrogens and men - this is a topic which has been neglected for quite some time and it is only relatively recently that discussion of it has intensified remarkably. The discussion has not been restricted to the scientific community. In former times, the role of estrogens in male physiology received little attention since androgens clearly have a dominant role. It is now becoming more and more evident that estrogens are far more important in the male than we had supposed (HABENICHT 1998).
TL;DR: A number of new antiepileptic drugs have been developed which include gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, topiramate and felbamate, all of which are currently in use.
Abstract: Antiepileptic drugs have been the mainstays of the treatment of patients with epilepsy. From 1978 to 1993 the primarily used antiepileptic drugs have been Phenytoin, carbamazepine, barbiturates and primidone, benzodiazepines, valproic acid and ethosuximide. Recently a number of new antiepileptic drugs have been developed which include gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, topiramate and felbamate. Unfortunately, early experience with felbamate was associated with an unacceptably high incidence of aplastic anaemia (Pennell et al. 1995) and chemical hepatitis, and in August of 1994 the manufacturer and the United States Federal Drug Administration recommended that, if clinically possible, patients be withdrawn from felbamate. Fortunately, the remaining newly developed antiepileptic drugs have been approved in many countries and are currently in use.