Showing papers in "Advances in Experimental Medicine and Biology in 1988"
TL;DR: Non invasive infrared spectroscopy is a well established technique for monitoring changes in the oxygenation status of tissues by observing the absorption of haemoglobin and cytochrome aa3 respectively and it has normally not been possible to quantitate the observed changes.
Abstract: Non invasive infrared spectroscopy is a well established technique for monitoring changes in the oxygenation status of tissues (1). The technique has in particular been successfully employed to monitor changes in cerebral blood and tissue oxygenation by observing the absorption of haemoglobin and cytochrome aa3 respectively. Because of the highly light scattering nature of the tissues studied, it has normally not been possible to quantitate the observed changes.
470 citations
TL;DR: In this article, the authors produce spontaneously diabetic rats from normal rats by repeating the selective breeding using glucose intolerance as the selection index, the rats are called GK rats and now they have the 37th generation.
Abstract: We produce spontaneously diabetic rats from normal rats by repeating the selective breeding using glucose intolerance as the selection index. The rats are called GK rats and now we have the 37th generation. In this paper, characteristic features, insulin secretion and the effect of obesity will be presented.
175 citations
TL;DR: Dendritic cells in lymphoid organs and related cells in non-lymphoid tissues play a pivotal role in the induction of T lymphocyte responses, and stimulate primary immune responses in culture and in vivo, and trigger allograft rejection.
Abstract: Dendritic cells (DC) in lymphoid organs and related cells in non-lymphoid tissues play a pivotal role in the induction of T lymphocyte responses (reviewed in Austyn, 1987). DC stimulate primary immune responses in culture and in vivo, and trigger allograft rejection. However, their mode of entry to the tissues and subsequent fate, and the significance of apparently mature DC in blood is unclear.
137 citations
TL;DR: Stress is a ubiquitous feature of life and its prevalence as a factor in health and disease is difficult to ascertain, but it is arguably a significant risk to the well being of the overall population.
Abstract: Stress is a ubiquitous feature of life Although its prevalence as a factor in health and disease is difficult to ascertain, it is arguably a significant risk to the well being of the overall population Stress and the response to stressful events, on the other hand, have played an important part in human survival and evolution From earliest times, people have dealt with harsh elements and adverse situations requiring both behavioral and physiological responses to protect themselves and their societies
97 citations
TL;DR: Sialic acid O-acetyl groups are also involved in immunological processes by modifying the antigenicity of glycoproteins and polysaccharides or by contributing to the specificity of tumor antigens.
Abstract: Sialic acids, comprising a group of N- and O-acyl as well as O-methyl and O-sulfate derivatives of neuraminic acid, are differently linked to various sugars of glycoproteins and gangliosides. Thus, the great molecular variety already existing in the asialo-portion of glycoconjugates is much increased by the addition of sialic acids. This structural diversity may be mirrored by a high antigenic diversity of the oligosaccharide part of complex carbohydrates. However, not much is known of such an influence of the sialic acid moieties of glycane chains, although antibodies against many non-sialylated oligosaccharides are known. In most cases investigated so far, sialic acids reduce or even prevent antigenicity of oligosaccharide chains and of the protein or lipid parts of glycoconjugate molecules, respectively. Enzymic removal of sialic acid or reduction of its carboxylic group to an alcohol residue alters or significantly increases the antigenicity. In contrast to this masking effect, sialic acids have been found to act as antigenic determinants. N-Acetylneuraminic acid in different linkages to other sugars is an essential component of various antigens in human erythrocytes, and N-glycolylneuraminic acid determines the blood group specificity of East-Asian dogs. The latter sialic acid also plays a role in immunological processes in man. N-Glycolylneuraminic acid probably cannot be synthesized in man, but is derived from the foodstuffs and incorporated into tissue glycoconjugates in small quantities. Sialic acid O-acetyl groups are also involved in immunological processes by modifying the antigenicity of glycoproteins and polysaccharides or by contributing to the specificity of tumor antigens. Evidence for a role of the multiple forms of sialic acids as differentiation antigens is accumulating.
90 citations
TL;DR: According to the results, keratinocyte transglutaminase participation in the biochemical pathway leading to programmed cell death (apoptosis), a basic cellular phenomenon of physiological significance, may be one of these functions.
Abstract: Although several details are still missing, the biological role of two of the three well characterized transglutaminases in mammals, namely blood coagulation factor XIII and keratinocyte transglutaminase, is established. The function of the third one called the tissue type is still an enigma. Its constant localization in endothelial and smooth muscle cells of all organs, in heart muscle, in medullary interstitial and mesangial cells of kidney, and its induction in a number of other cell types under a variety of conditions suggest multiple functions. According to our results its participation in the biochemical pathway leading to programmed cell death (apoptosis), a basic cellular phenomenon of physiological significance, may be one of these functions.
83 citations
TL;DR: An analysis of the interaction between circulatory convective and tissue diffusive O2 transport that explains how VO2 max is set by the integrated response to each and every step in the O2 Transport chain from atmosphere to mitochondria is developed.
Abstract: When one considers the pathway for transfer of O2 from the atmosphere to the mitochondria, several distinct and sequential steps are classically identified: 1) convective gas flow of O2 to the alveoli by ventilation 2) diffusive gas mixing and transfer across the blood gas barrier into the capillary blood, 3) convective transport in the blood to the peripheral tissues, and 4) diffusive movement out of the tissue capillary to the mitochondria where O2 is utilized
80 citations
TL;DR: Diurnal variation in pituitary-adrenal function is based upon an endogenous oscillator, although both the light-dark cycle and the anticipation of food entrain the rhythm, which results in high levels of glucocorticoids in the blood.
Abstract: Stress-induced release of glucocorticoids is one of two modes of operation of the pituitary-adrenal axis, the other being the diurnal variation of glucocorticoid levels. Both operating modes are, of course, driven by CNS release of the releasing factor, CRH, in combination with other modulators such as vasopressin and oxytocin (Vale, this volume; Plotsky, this volume; (1)). However, stress-induced release is due to environmental and experiential factors such as heat, cold, anxiety, trauma and exertion, and it results in high levels of glucocorticoids in the blood. On the other hand, diurnal variation in pituitary-adrenal function is based upon an endogenous oscillator (2), although both the light-dark cycle and the anticipation of food entrain the rhythm (3, 4).
65 citations
TL;DR: The present chapter summarizes the findings with lipoxins (LX) in spasmogenic assays and in the intact microvasculature of the hamster cheek pouch and the pharmacodynamics and structure activity relationships forlipoxins in smooth muscle preparations.
Abstract: The present chapter summarizes our findings with lipoxins (LX) in spasmogenic assays and in the intact microvasculature of the hamster cheek pouch. The initial observations1,2 were made in experiments using lipoxins isolated from human leukocytes. With the aid of synthetic compounds3, it has been possible to further explore the pharmacodynamics and structure activity relationships for lipoxins in smooth muscle preparations.
64 citations
TL;DR: Carohydrate sequence analysis shows that salivary mucins exhibit considerable polydispersity, great diversity and remarkable structural flexibility not only among animal species but also within the same mucin molecule.
Abstract: Mucus is a complex exocrine secretion that covers the epithelial linings of higher animals. This secretion is derived from different types of epithelial glands which are composed of a variety of specialized cells. Consequently, tear, sputum, saliva, gastric juice, colonic and cervical mucus are all composed of a heterogeneous mixture of secretory products. Salivary mucus is produced by several glands (Table I). The bulk of it is derived from three main organ glands, namely the parotid which is serous in nature, the submandibular which contains both mucous and serous type acini, and the predominantly mucus secreting sublingual gland (1–5). In addition, numerous so-called minor salivary glands are dispersed throughout the oral soft tissue (6,7). These labial glands are composed mainly of mucous secreting cells, and consequently are a major source of the total mucins in saliva although they comprise only some 10% of the salivary volume produced daily. Mixed salivary secretions contain some 99.5% water; the remainder is made up of glycocon jugates, lipids, proteins, ions and small metabolites (8–12) . Due to its great variety of components, saliva plays multiple physiological roles.
63 citations
TL;DR: Mental retardation and behavioral deficits, such as hyperactivity, jitteriness, irritability and marked attentional and learning problems, are consistently observed in children who were exposed to alcohol in utero.
Abstract: It is now generally acknowledged that pre- and/or postnatal environmental factors, such as stress and drugs, can exert long-lasting neurobehavioral effects in the individual. These factors may influence the development of central regulatory systems by acting directly on the fetal brain or indirectly through changes in the internal environment of the mother and fetus. The Fetal Alcohol Syndrome which has been recognized as a clinical entity for the past 15 years (1) is a case in point. Adverse effects of maternal alcohol consumption during pregnancy on growth and development of the offspring have been well documented in humans and laboratory animals (2). Mental retardation and behavioral deficits, such as hyperactivity, jitteriness, irritability and marked attentional and learning problems, are consistently observed in children who were exposed to alcohol in utero (3).
TL;DR: Regardless of the A, B, H, Le(a), Le(b), I and i activity, purified water-soluble blood group glycoproteins from human ovarian cyst fluid have a similar overall structure.
Abstract: The chemical structures of the blood group A, B, H, Lea, Leb, I and i determinants in water soluble blood group substances isolated from human ovarian cyst fluid have been studied for over four decades and are well established (1–10). However, the internal structure of the carbohydrate moiety had not been approached until base was applied to cleave the o- glycosidic linkage between the GaAc of the carbohydrate moiety and Thr and Ser of the protein core (8,11–15). The proposed composite structure of the carbohydrate side chains of blood group A, B, H, Lea and Leb substances (5,16,17) and of precursor substances with I and i determinants (18) shown in Fig. 1 were inferred from the mechanism of the alkaline s-elimination and peeling reactions, together with the structures of the oligosaccharide fragments isolated (16) . More evidence is needed to confirm these carbohydrate internal structures. s-elimination of intact blood group substances Fig. 1 (A) Proposed composite oligosaccharide structure (2,16,19) showing the relationship of the various blood group determinants and genes involved. Asterisk denotes that A substances have not been examined for oligosaccharides in this region (17).
TL;DR: Lectins that bind to Makela’s group II sugars are Gal-specific whereas those reacting with sugars of group III are Man and/or Glc-specific lectins, while Fucose-binding lectins are specific for group I sugars and Lectin binding sugars belonging to group IV have not yet been reported.
Abstract: Lectins are carbohydrate-binding proteins of nonimmune origin, which have been widely used in the fields of cell biology, biochemistry and histochemistry to isolate and/or to characterize cell surface carbohydrates(1–3). Lectins require configurational and structural complementarity of sugars for interaction to occur. All lectin molecules have two or more carbohydrate binding sites, a property essential to their ability to agglutinate cells or to precipitate complex carbohydrates(1, 2, 4). Until the early seventies, the carbohydrate specificities of lectins were mainly determined by the abilities of monosaccharides or their glycosides to inhibit lectin-induced haemagglutination(1, 4). Makela(5), in the late fifties, divided lectin-reactive monosaccharides into four classes, based on their configuration at C-3 and C-4 of the pyranose form, as shown in Fig. 1. Lectins that bind to Makela’s group II sugars are Gal-specific whereas those reacting with sugars of group III are Man and/or Glc-specific lectins. Fucose-binding lectins are specific for group I sugars. Lectins binding sugars belonging to group IV have not yet been reported.
TL;DR: Although the di- and polyamine oxidases of plants are apparently limited in their distribution, in some species they are remarkably active.
Abstract: Although the di- and polyamine oxidases of plants are apparently limited in their distribution, in some species they are remarkably active. Earlier work on these enzymes has been summarized by Smith (1985a), Morgan (1985), Rinaldi et al., (1986), and Mondovi and Avigliano (1987).
TL;DR: The selectivities of various dopamine agonists and antagonists for dopamine D1 and D2 receptors were obtained by comparing their relative dissociation constants for inhibiting the binding of [3H]SCH 23390 at D1 receptors (calf caudate nucleus) and at D 2 receptors (pig anterior pituitary tissue).
Abstract: The selectivities of various dopamine agonists and antagonists for dopamine D1 and D2 receptors were obtained by comparing their relative dissociation constants for inhibiting the binding of [3H]SCH 23390 at D1 receptors (calf caudate nucleus) and at D2 receptors (pig anterior pituitary tissue). The most selective agonists were SK&F 38393 (for D1) and (+)-PHNO (for D2), while the most selective antagonists were SCH 23390 (for D1) and raclopride or eticlopride (for D2).
TL;DR: From this network of interactions, it can be deduced that several of these sites can be occupied by their respective ligands simultaneously and that each of the 5 or more types of site must be physically separate on the receptor structure.
Abstract: The GABAA receptorreceptor is the major molecular site of the ubiquitous inhibitory acEivities of the brain, being present on the great majority of mammalian brain neurones (1). Electrophysiological studies and, especially, recent patch-clamp studies on cultured neurones (2,3) have established that at these sites GABA opens a chloride channel which is integrally associated with its receptor. Further, the GABAA receptor at brain synapses is known to be a site of action of several pharmacologically important classes of drugs. Pharmacological and ligand-binding studies (reviewed in Ref. 4) have identified at least 5 types of binding site on this receptor: (i) the GABA agonist/antagonist site; (ii) the benzodiazepine site, which itself is complex, having interactions with both anxiolytic agonists and anxiogenic “inverse agonists” (5); (iii) the picrotoxin site, where agents such as picrotoxin (5) or t-butylbicyclophosphorothionate (6) block the GABA-activated channel; (iv) the depressant site, recognising the CNS-depressant barbiturates and certain other depressant drugs which prolong the lifetime of the GABA-activated channel (3); this site, also, appears to be multiple, since certain steroids (7), the anaesthetic propanadid (8) and avermectin Bla (9,10) act similarly to depressants in some but not all ways; (v) sites binding the channel-permeating anions (but not other ions) (2,4). Each of these types of ligand site can interact allosterically with one or more of the other types (4). From this network of interactions, it can be deduced that several of these sites can be occupied by their respective ligands simultaneously and that each of the 5 or more types of site must be physically separate on the receptor structure.
TL;DR: It is now well accepted that in vertebrate species isografteds and autografts are usually endured, but allograft’s and xenogirafts (heterograftS) are uniformly rejected.
Abstract: Inflammation and immunity are intimately related processes and in the vertebrate species most inflammatory responses have an immunological component (1). This concept also applies to transplantation biology where an acute or chronic rejection may be biologically very similar to an inflammatory response, although the basis of rejection of a graft is immunologically mediated. It is now well accepted that in vertebrate species isografts and autografts are usually endured, but allografts and xenografts (heterografts) are uniformly rejected. A few exceptional circumstances exist in nature where an allograft is normally accepted by the host, at least for a prolonged period of time. One of these unusual allograft tolerances in nature occurs routinely during mammalian pregnancy.
TL;DR: A tumor cell autocrine motility factor (AMF) is secreted by the tumor cells and binds to a cell surface receptor resulting in a profound stimulation of cell locomotion which may play a major role in the autonomous invasive behavior of tumor cells.
Abstract: Cancer invasion and metastases is a complex multistep process. In order for a tumor cell to successfully traverse all the steps of this process and initiate a metastatic colony, it must express the right combination of gene products. Such gene products may include proteins which regulate cell interaction with the basement membrane and cell motility. Tumor cells attach to the basement membrane glycoprotein laminin via the cell surface laminin receptor. The human laminin receptor was purified and molecularly cloned. The level of laminin receptor mRNA is a variety of human carcinoma cells correlated with the number of laminin receptors on the cell surface of these cells. Following attachment to the basement membrane, the tumor cell next secretes proteases which may degrade type IV collagen. A genetic linkage between type IV collagenase secretion and metastases was studied using our new genetic system for inducing metastases employing the ras oncogene. Following attachment and local proteolysis, the third step of invasion is tumor cell motility. We have isolated a tumor cell autocrine motility factor (AMF). This factor is secreted by the tumor cells and binds to a cell surface receptor resulting in a profound (greater than 100x) stimulation of cell locomotion. AMF may play a major role in the autonomous invasive behavior of tumor cells.
TL;DR: The oxygenation and energy states of brain tissues were measured simultaneously by near-infrared photometry and nuclear magnetic resonance spectroscopy in situ and in both cat and dog, the critical hemoglobin oxygenation was 10%, below which the ratio of phosphocreatine to inorganic phosphate started to fall.
Abstract: There is no doubt that tissue oxygen concentration is the critical determinant in the energy metabolism of living tissues. The concept of critical oxygen concentration, which was introduced to emphasize this, has been defined as the oxygen concentration at which the respiration rate of the tissue starts to obey first order kinetics rather than zero-order with respect to oxygen. The critical oxygen concentration values reported for isolated mitochondria and tissue show discrepancies. The tissue oxygen gradient can explain the variation between the two.
TL;DR: It has been now accepted that there are at least four distinct sialoglycoproteins in human erythrocyte membranes, and three of them are designated as glycophorin A, B and C.
Abstract: The name of glycophorin was given by Marchesi et al. (1972) to the major sialoglycophorin of human erythrocyte membranes, known earlier as the glycoprotein carrying blood group M and N determinants and receptors for agglutinins of influenza viruses (Baranowski et al., 1959; Romanowska 1959; Klenk & Uhlenbruck, 1960; Kathan et al., 1961; Springer et al., 1966). Fractionation of the erythrocyte membranes by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and visualization of sialoglycoproteins with periodic acid-Schiff (PAS) reagent give a complex pattern of bands which may differ in details, depending on electro- phoretic conditions. It has been now accepted that there are at least four distinct sialoglycoproteins in human erythrocyte membranes. Furthmayr et al. (1975) designated three of them as glycophorin A, B and C, in order of their decreasing amount in the membrane. Anstee et al. (1979) denoted them glycoprotein α, β, γ and δ, in order of their decreasing molecular weight. Dahr et al. (1978c) used other designations. The more numerous bands seen in SDS-PAGE correspond to monomers of the sialoglycoproteins and to homo- and heterodimers (and higher oligomers) formed by the most abundant glycophorins A and B (Fig. 1).
Journal Article•
TL;DR: In this article, the binding properties of lectins were characterized by quantitative precipitin assay, which can also be used to classify these lectins based on determinant structure rather than monosaccharide inhibition pattern.
Abstract: Grouping of lectin binding properties, based on determinant structure rather than monosaccharide inhibition pattern, should facilitate the selection of lectins as structural probes for glycans as well as for the interpretation of the distribution and the properties of the carbohydrate chains on the cell surface. Based on the binding specificities studied with glycan by precipitin-inhibition, competitive-binding and hemagglutinin-inhibition assays, twenty Ga1 and/or Ga1NAc specific lectins have been divided into six classes according to their specificity for the disaccharide as all or part of the determinants and Ga1NAc alpha 1----Ser(Thr) of the peptide chain. The differential affinities of these lectins were characterized by quantitative precipitin assay. Abbreviation of the following six lectin determinants can also be used to classify these lectins. (1) F determinant (GalNAc alpha 1----3GalNAc, Forssman specific disaccharide). (2) A (Af) determinant (GalNAc alpha 1----3Gal, Human blood group A specific disaccharide; Af, fucosylated A, (GalNAc alpha 1----3 [LFuc alpha 1----2]Gal). (3) Tn determinant (GalNAc alpha 1----0 to Ser (Thr) of the protein core, Tn antigen). (4) T determinant (T antigen, Gal beta 1----3GalNAc alpha 1----0 to Ser (Thr) of the protein core, the mucin type sugar sequence on the human erythrocyte membrane or Gal beta 1----3GalNAc beta 1---- at the nonreducing end of ganglioside). (5) I and II determinants (human blood group type I and II carbohydrate sequences). Most of the lectins reactive to Gal beta 1----4GlcNAc (II) are also reactive to Gal beta 1----3GlcNAc (I). Lectin I (II) determinants (i.e. Gal beta 1----3 (4) GlcNAc residues) can be found at the nonreducing end of the carbohydrate chains derived from either N-glycosidic or O-glycosidic linkages. (6) B determinant (Gal alpha 1----3Gal, Human blood group B specific disaccharide). Their carbohydrate specificities are classified as following: (Table see text). The differential binding properties of lectins can be defined from comparisons of their carbohydrate specificities listed above.
TL;DR: It is concluded that during physical exercise degranulation of PMN leukocytes occurs and the fact that phorbol-stimulated chemiluminescence is decreased after running demonstrates an impaired capability of white cells to generate oxygen radicals.
Abstract: In recent years, many forms of physical exercise have been considerably propagated in western societies. Therefore, many investigators have turned their interest towards the metabolic alterations, induced by enhanced physical training. Moorthy and Zimmermann reported an increase in the number of circulating leukocytes (1) during prolonged exercise, whereas Hedfors et al. (2) showed a phase of lymphocytosis following short-time exercise. Body core temperature was found to be increased after lengthy exercise (3). Furthermore, an increment of plasma levels of acute-phase proteins, such as C-reactive protein, ceruloplasmin, fibrinogen, and alpha1-antitrypsin, has been demonstrated (4). Studies in subjects on long-term physical training showed chronic depression of plasma iron (5) and zinc (6) levels. Even frank anemia has been reported in joggers and competition runners (5). Cannon and Kruger were the first to relate this metabolic pattern, which displays a remarkable similarity to the physiological response to an infectious or inflammatory challenge, to an increased release of endogenous pyrogen, which is secreted by monocytes and macrophages (7).
TL;DR: Highly trained subjects have elevated basal concentrations of ACTH and cortisol and a blunted response to exogenous corticotropin releasing hormone and these data are compatible with mild sustained hypercortisolism in highly trained runners.
Abstract: Muscular activity is a component of the “fight or flight” response. Hormones which play an important role in the preservation of homeostasis are activated in response to acute exercise (1–9). Physical training appears to lead to a reduction in the “stress response” to a given workload (8,9). What role, this modulation of the “stress response” plays in the improved performance of trained athletes remains an intriguing question. We report in this brief review the response of several pituitary and adrenal hormones to various intensities of acute treadmill exercise stress. The effect of physical training on these hormonal responses was studied by comparing the responses of sedentary, untrained subjects to the responses of two groups of runners with different degrees of fitness (8).
TL;DR: The methods for performance of the major parameters related to quantitation of TS inhibition resulting from fluoropyrimidine administration to patients, methods equally applicable to preclinical studies are detailed.
Abstract: This report details our methods for performance of the major parameters related to quantitation of TS inhibition resulting from fluoropyrimidine administration to patients, methods equally applicable to preclinical studies. Sampling of tumors before and after drug treatment is done by 4 mm disposable punch biopsy or forceps biopsy via subcutaneous tunneling. Homogenates are prepared using N2 or polytron-mincing. Cytosolic free TS is measured by either the tritium-release method for small biopsies or by [3H]FdUMP ligand-binding. FdUMP and dUMP are separated by DEAE-cellulose column and measured by competitive binding and [14C]dTMP synthesis by the Moran methods. Total, postFUra TS is measured by pre-incubation dissociation of FdUMP-bound TS after neutral charcoal removal of cytosolic ligands. H4PteGlu and CH2-H4PteGlu are measured by the Priest method using L. Casei TS. The materials and methods are described in sufficient detail to permit wide application of this approach.
TL;DR: Fever or exercise-induced hyperthermia, will elevate oxygen demand and amplify the hypoxic stress of a mammal at high altitude or with cardiopulmonary disease, and hypothermia could be beneficial to any animal faced with a limited oxygen supply.
Abstract: It is well established that altered body temperature (Tb) has an exponential effect on the oxygen consumption (\({\dot V}\)O2) of resting animals (Krogh, 1914). Alterations of Tb over a range larger than 20°C are routine for ectothermic vertebrates. The range of altered core Tb is smaller for homeotherms but is still significant in hyperthermia and hypothermia. In general, a l°C change in Tb causes an 11% change in metabolic rate (Q10 = 2.5). Consequently, fever or exercise-induced hyperthermia, will elevate oxygen demand and amplify the hypoxic stress of a mammal at high altitude or with cardiopulmonary disease. Conversely, hypothermia could be beneficial to any animal faced with a limited oxygen supply.
TL;DR: Results of recent studies on the isolation, biosynthesis, stereochemistry and biological activities of this new series of compounds (lipoxins) are described.
Abstract: The oxygenation of arachidonic acid and other polyunsaturated fatty acids by a wide variety of cell types results in the formation of several structurally distinct classes of biologically active compounds1,2. These compounds include the prostaglandins, thromboxanes, leukotrienes, and other oxygenated derivatives of polyunsaturated fatty acids. A most recent addition to this family of biologically active compounds is the lipoxins (Figure 1). Leukotrienes and lipoxins are formed by mechanisms which involve initial oxygenation of free fatty acids by lipoxygenases. In general, lipoxygenase products display a wide range of actions and appear to be involved in immunity, the regulation of inflammation, and other physiological and pathophysiological processes. In this chapter we describe results of recent studies on the isolation, biosynthesis, stereochemistry and biological activities of this new series of compounds (lipoxins).
TL;DR: The present findings lend support to the hypothesis that transiently open junctions surrounding the dividing endothelial cells provide the major pathway through which macromolecules enter the subendothelial space to result in lipid accumulation.
Abstract: Atherosclerosis is characterized by focal areas of lipid accumulation and intimal smooth muscle cell proliferation. Atherosclerotic lesions tend to develop in preferential areas in the aortic tree,1 where transendothelial macromolecular permeability is high as indicated by an enhanced uptake of the protein-binding azo dye Evans Blue in vivo.2–4 These so-called blue areas have been shown to be associated with an increased rate of endothelial cell turnover3,5 and an enhanced permeability to low density lipoproteins (LDL).6 The subendothelial accumulation of unesterified cholesterol has been hypothesized to be an initial event in atherogenesis.7 The mechanism by which macromolecules such as LDL or albumin enter the arterial wall, however, is still not completely understood.
TL;DR: There is great hope for reducing the severity of injury produced by these enzymes and, therefore, in decreasing the risk for development of the debilitating diseases associated with abnormal proteolysis by neutrophil proteinases.
Abstract: Human neutrophils utilize a variety of destructive enzymes during the process of phagocytosis. These include proteinases, phosphatases, glycosidases, nucleases, and oxidases. The major enzymes have been determined to be elastase, cathepsin G, myeloperoxidase, and lysozyme (1), while minor proteins include collagenase, lactoferrin, alkaline phosphatase, and a myriad of other proteins.
TL;DR: In summary, 5HT, ACh, NE, E and DA appear to stimulate hypothalamic CRH secretion whereas activation of the GABA/BZD system seems to decrease the responsivity of the CRH neuron to stimulatory neurotransmitters.
Abstract: In summary, 5HT, ACh, NE, E and DA appear to stimulate hypothalamic CRH secretion whereas activation of the GABA/BZD system seems to decrease the responsivity of the CRH neuron to stimulatory neurotransmitters (Fig. 6). Hypothalamic CRH released from the hypothalamic neuron not only activates the HPA axis, but also stimulates the locus coeruleus-norepinephrine system (LC) and the central sympathetic system (CSS). CRH also induces secretion of hypothalamic POMC gene-derived peptides, such as ACTH, beta-EP, alpha-MSH and CLIP. These peptides as well as CRH itself, decrease the responsivity of the CRH neuron to stimulatory inputs. In addition, glucocorticoids restrain the activity of both the CRH neuron and the locus coeruleus and may also inhibit the secretion of POMC gene-derived peptides by the POMC neurons of the arcuate nucleus. Hypothalamic CRH secretion is regulated also by a number of mediators of the immune response, such as IL-1, IL-2, TNF-alpha and PGF2 alpha, PAF and EGF. Although the physiologic significance of this regulation is largely unknown, it is tempting to speculate that cytokines and mediators of inflammation released in vivo may activate the HPA axis to trigger a glucocorticoid-mediated counter-regulatory mechanism to restrain the immune system (Fig. 7). (Formula: see text). Fig. 7. Schematic representation of the interactions between the HPA axis and the immune system. Continuous lines represent stimulatory inputs and interrupted lines represent inhibitory inputs. In conclusion, our in vitro hypothalamic organ culture system allowed us to examine the regulation of CRH secretion in a direct and specific manner. Some of our observations may help with better understanding of the role played by CRH in the complex symptomatology of stress. In making extrapolations and interpretations from the in vitro data, however, we should try to keep in mind the words of Claude Bernard, "... If we break up a living organism by isolating its different parts it is only for the sake of ease in analysis and by no means in order to consider them separately. Indeed when we wish to ascribe to a physiological quality its value and true significance we must always refer it to this whole and draw our final conclusions only in relation to the effects in the whole".
TL;DR: Interference with polyamine biosynthesis by analog-mediated regulatory mechanisms represents a viable alternative to the use of specific enzyme inhibitors as an antiproliferative strategy and the continued preclinical development of available analogs might proceed most productively by targeting large cell lung carcinoma and melanoma.
Abstract: Our current rationale for targeting polyamines as a mechanism-based drug discovery initiative is based on several diverse yet interrelated considerations (Table 1) some of which derive from findings to be reviewed here. Of these, the most critical are (a) the strict dependence of proliferating cells on polyamine availability (b) the increased rate of polyamine biosynthesis and transport associated with neoplastic tissues relative to their normal counterparts and (c) the novelty of polyamine biosynthesis and/or function as a departure from more cyto-toxic DNA-directed approaches. While admittedly, an absolute basis for selectivity has not yet been defined, recognition must be given to the fact that no chemotherapeutic strategy described to date is wholly selective for tumor tissue and yet total curability of a number of malignant diseases can be achieved. We believe this justifies the evaluation of new and novel approaches even in the absence of absolute metabolic rationale for selective tumor cell kill. Although still confined to animal model systems, encouraging antitumor data with polyamine analogs lend credence to this belief (Bergeron et al., 1988).