scholarly journals A histochemical principle bearing on correctness of diagnosis in storage diseases.

1989 ◽  
Vol 37 (2) ◽  
pp. 217-222
Author(s):  
M Wolman
Keyword(s):  
Metabolic Disorder ◽  
Storage Disease ◽  
Storage Diseases ◽  
Multiple Substrates ◽  
Histochemical Test ◽  
Wide Range ◽  
Storage Cells ◽  
Tentative Diagnosis ◽  
Single Enzyme ◽  
Main Substrate

A principle is proposed which may help pathologists avoid errors in diagnosis of storage diseases. Tissues from patients in whom a tentative diagnosis of a metabolic disorder has been made often store a number of metabolites in the cells. The presence of these metabolites can occur in single-enzyme or activator defects as a result of the following causes: (a) deposition of metabolites situated near the main substrate of the defective enzyme in the catabolic path, and compounds which were changed after they were deposited; (b) presence of multiple substrates for this enzyme; (c) co-deposition of molecules bound to the main substrates; (d) existence of multiple substrates for a single defective activator molecule. In contrast to these causes, variability in processes not associated with a single-enzyme or activator deficiency may be due to the following: (e) inhibition of multiple hydrolases by drugs or metabolites; (f) localization of substrates and hydrolases in different compartments; (g) multiple enzyme deficiencies; (h) concentration of metabolites beyond the catabolic capacity of cells. According to the proposed principle, diagnosis of storage disease resulting from a single enzyme deficiency can be negated if a wide-range histochemical test shows that the main substrate of a deficient enzyme is not present in some primary storage cells. The validity of the principle and possible pitfalls are discussed.

scholarly journals THE EFFECT OF CHRONIC HYPERGLYCEMIA ON THE STATE OF MUSCULOSKELETAL SYSTEM (LITERATURE REVIEW)

2021 ◽  
Vol 21 (1) ◽  
pp. 184-187
Author(s):  
A.O. Ponyrko
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Bone Tissue ◽  
Musculoskeletal System ◽  
Metabolic Disorder ◽  
Skeletal System ◽  
Complex Disorders ◽  
Chronic Hyperglycemia ◽  
Wide Range

Diabetes mellitus is a metabolic disorder that today has become a threatening problem for human health. Its prevalence has been constantly increasing throughout the world over the past decades. Diabetes mellitus is regarded as an incurable metabolic disorder characterized by hyperglycemia, which is caused by defects in insulin secretion. This disease annually affects almost 3% of the total population of the planet. Chronic hyperglycemia causes dysfunction of various organs of the body, such as the eyes, kidneys, heart, blood vessels, and nerves. The most common complications of diabetes include lesions of the vessels of the eye, kidneys, lower limbs and nervous system. A high level of glucose in the blood causes the development of a wide range of pathological disorders, which affect bones as well. Recent studies have shown that diseases of the skeletal system are often observed in diabetes mellitus. Speaking about the effect of hyperglycemia on bones, the development of osteopenia and osteoporosis should be noted. In this regard, an important area of research is to study changes in the bone tissue in patients with type 1 diabetes mellitus and the mechanisms that lead to disruption of bone structure and metabolism. The article highlights the pathophysiological mechanisms of hyperglycemia action in type 1 diabetes that explains complex disorders of the organs of the musculoskeletal system. The detrimental effect of hyperglycemia results in marked degenerative changes in bone cells. The pathogenic effect of hyperglycemia on bone tissue is manifested in a decrease in bone mineral density that is due to the lack of insulin and, as a consequence, significant metabolic disorders, a decrease in bone mass, inhibition of bone tissue formation, a significant decrease in the trace element composition of bone. The combination of these factors creates the appropriate pathomorphological basis for the development of diabetic osteopathy. The article highlights the mechanism of action of hyperglycemia on skeletal system in order to stimulate to a more detailed investigation of diabetes mellitus in experimental animals.

scholarly journals Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases

2019 ◽  
Vol 20 (2) ◽  
pp. 327 ◽  
Author(s):  
Paola Faverio ◽  
Anna Stainer ◽  
Federica De Giacomi ◽  
Serena Gasperini ◽  
Serena Motta ◽  
...  
Keyword(s):  
Sleep Apnea Syndrome ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Airway Disease ◽  
Pulmonary Involvement ◽  
Molecular Pathways ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Obstructive Sleep ◽  
Wide Range

Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Pulmonary involvement includes interstitial lung disease in Gaucher’s disease and Niemann-Pick disease, obstructive airway disease in Fabry disease and ventilatory disorders with chronic respiratory failure in Pompe disease due to diaphragmatic and abdominal wall muscle weakness. In mucopolysaccharidosis and mucolipidoses, respiratory symptoms usually manifest early in life and are secondary to anatomical malformations, particularly of the trachea and chest wall, and to accumulation of glycosaminoglycans in the upper and lower airways, causing, for example, obstructive sleep apnea syndrome. Although the molecular pathways involved vary, ranging from lipid to glycogen and glycosaminoglycans accumulation, some clinical manifestations and therapeutic approaches are common among diseases, suggesting that lysosomal storage and subsequent cellular toxicity are the common endpoints.

scholarly journals Molecular analysis of the Drosophila EGF receptor homolog reveals that several genetically defined classes of alleles cluster in subdomains of the receptor protein.

Genetics ◽  
1994 ◽  
Vol 137 (2) ◽  
pp. 531-550 ◽  
Author(s):  
R Clifford ◽  
T Schüpbach
Keyword(s):  
Molecular Analysis ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Receptor Protein ◽  
Loss Of Function ◽  
Developmental Processes ◽  
Multiple Substrates ◽  
Wide Range ◽  
Mechanistic Basis ◽  
Mutant Phenotypes

Abstract Mutations in the torpedo gene, which encodes the fruitfly homolog of the epidermal growth factor receptor (DER), disrupt a variety of developmental processes in Drosophila. These include the survival of certain embryonic ectodermal tissues, the proliferation of the imaginal discs, the morphogenesis of several adult ectodermal structures and oogenesis, torpedo is genetically complex: a number of alleles of the gene differentially affect the development of specific tissues, such as the eye, wing, bristles and ovary. In addition, torpedo mutations exhibit interallelic complementation. Molecular analysis of 24 loss-of-function mutations in the torpedo gene provides insights into the mechanistic basis of its genetic complexity. We observe an intriguing correlation between molecular lesions and mutant phenotypes. Alleles that differentially affect specific developmental processes encode receptors with altered extracellular domains. Alleles that fully or partially complement a wide range of embryonic and postembryonic torpedo mutations encode receptors with altered intracellular domains. From these findings we conclude the following. First, the torpedo protein may be activated by tissue-specific ligands. Second, the torpedo receptor tyrosine kinase may phosphorylate multiple substrates. Third, signal transduction by torpedo appears to require the physical association of receptors. Finally, the extracellular domain of the Torpedo protein may play an essential role in mediating receptor-receptor interactions.

scholarly journals Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease

2010 ◽  
Vol 38 (6) ◽  
pp. 1453-1457 ◽  
Author(s):  
Alessandra d'Azzo ◽  
Erik Bonten
Keyword(s):  
Lysosomal Enzymes ◽  
Molecular Mechanisms ◽  
Storage Disease ◽  
Hydrolytic Enzymes ◽  
Lysosomal Storage ◽  
Serine Carboxypeptidase ◽  
Primary Defect ◽  
Apparent Lack ◽  
Storage Diseases ◽  
Lysosomal System

The lysosomal system comprises a specialized network of organelles crucial for the sorting, digestion, recycling and secretion of cellular components. With their content of hydrolytic enzymes, lysosomes regulate the degradation of a multitude of substrates that reach these organelles via the biosynthetic or the endocytic route. Gene defects that affect one or more of these hydrolases lead to LSDs (lysosomal storage diseases). This underscores the apparent lack of redundancy of these enzymes and the importance of the lysosomal system in cell and tissue homoeostasis. Some of the lysosomal enzymes may form multiprotein complexes, which usually work synergistically on substrates and, in this configuration, may respond more efficiently to changes in substrate load and composition. A well-characterized lysosomal multienzyme complex is the one comprising the glycosidases β-gal (β-galactosidase) and NEU1 (neuramidase-1), and of the serine carboxypeptidase PPCA (protective protein/cathepsin A). Three neurodegenerative LSDs are caused by either single or combined deficiency of these lysosomal enzymes. Sialidosis (NEU1 deficiency) and galactosialidosis (combined NEU1 and β-gal deficiency, secondary to a primary defect of PPCA) belong to the glycoprotein storage diseases, whereas GM1-gangliosidosis (β-gal deficiency) is a glycosphingolipid storage disease. Identification of novel molecular pathways that are deregulated because of loss of enzyme activity and/or accumulation of specific metabolites in various cell types has shed light on mechanisms of disease pathogenesis and may pave the way for future development of new therapies for these LSDs.

scholarly journals Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases

2021 ◽  
Vol 22 (11) ◽  
pp. 5778
Author(s):  
Francesco Callea ◽  
Paola Francalanci ◽  
Isabella Giovannoni
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Phase ◽  
Rough Endoplasmic Reticulum ◽  
Storage Disease ◽  
Acute Phase Reactant ◽  
Storage Diseases ◽  
Phase Reactant ◽  
Alpha 1 Antitrypsin ◽  
Encoding Genes ◽  
Liver Storage

Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).

scholarly journals Busulfan disposition below the age of three: alteration in children with lysosomal storage disease

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 1030-1034 ◽  
Author(s):  
G Vassal ◽  
A Fischer ◽  
D Challine ◽  
I Boland ◽  
F Ledheist ◽  
...  
Keyword(s):  
Young Children ◽  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Dose Range ◽  
Lysosomal Storage Diseases ◽  
Volume Of Distribution ◽  
Optimal Dosage ◽  
Lysosomal Storage ◽  
Acute Leukemias ◽  
Storage Diseases

Busulfan disposition is age-dependent with a higher clearance and a larger volume of distribution in children than in adults. The optimal dosage of busulfan needed to achieve bone marrow (BM) displacement in young children with malignant or nonmalignant disease remains to be defined. Using a gas chromatography-mass spectrometry assay, we evaluated plasma pharmacokinetics of busulfan in 33 children (median age, 9 months; range, 2 months to 2.75 years) with immune deficiencies, lysosomal storage diseases, acute leukemias, and malignant lymphohistiocytosis after an oral dose ranging from 0.9 to 2.6 mg/kg. The busulfan clearance (assuming a bioavailability of 1) ranged from 2.1 to 13.4 mL/min/kg with a mean of 6.8 mL/min/kg, which is higher than that reported in older children (4.5 mL/min/kg) and adults (2.9 mL/min/kg). Six children with lysosomal storage disease (5 with Hurler's disease, 1 with San Filippo's disease) had a prolonged elimination half-life (4.9 v 2.4 hours), a larger volume of distribution (3.4 v 1.2 L/kg) and a faster clearance (8.7 v 6.3 mL/min/kg) than the other 27 children. This suggests that a higher dose of busulfan will be required to achieve BM displacement in children with lysosomal storage disease. Over the dose range of 0.9 to 2.6 mg/kg, busulfan pharmacokinetics were linear. However, only 46% of the interpatient variation in systemic exposure could be ascribed to the dose. Given the wide interpatient variability in busulfan disposition, dose adjustment and drug monitoring will be needed to achieve the optimal dosage of busulfan in young children. The plasma busulfan levels required to achieve BM displacement need to be defined, especially in lysosomal storage diseases.

scholarly journals Mass extinctions past and present: a unifying hypothesis

2008 ◽  
Vol 5 (3) ◽  
pp. 2401-2423 ◽  
Author(s):  
S. A. Wooldridge
Keyword(s):  
Big Five ◽  
Terrestrial Ecosystems ◽  
Mass Extinctions ◽  
Ambient Conditions ◽  
Co2 Partial Pressure ◽  
Scientific Discussion ◽  
Dependent Inactivation ◽  
Wide Range ◽  
Extinction Event ◽  
Single Enzyme

Abstract. Enzymes are often referred to as the "agents of life" – a very apt term, since essentially all life processes are controlled by them. Typically, these enzymes only function across a narrow band of environmental conditions, particularly temperature and pH. Ambient conditions that challenge these operating conspecifics trigger enzyme dysfunction. Here, it is proposed that the pH-dependent inactivation of a single enzyme, urease, provides a unifying kill-mechanism for at least four of the "big five" mass extinctions of the past 560 million years. The triggering of this kill-mechanism is suggested to be sensitive to both gradualistic and catastrophic environmental disturbances that cause the operating pH of urease-dependent organisms to cross enzymatic "dead zones", one of which is suggested to exist at ~pH 7.9. For a wide range of oceanic and terrestrial ecosystems, this pH threshold coincides with an atmospheric CO2 partial pressure (pCO2) of ~560 ppmv – a level that at current CO2 emission trajectories may be exceeded as early as 2050. The urease hypothesis thus predicts an impending Anthropocene extinction event of equivalence to the "big five" unless future atmospheric pCO2 levels can be stabilised well below 560 ppmv. Immediate scientific discussion and testing is required to confirm the validity of the urease hypothesis.

scholarly journals Aromatic dimer dehydrogenases from Novosphingobium aromaticivorans reduce monoaromatic diketones

2021 ◽  
Author(s):  
Alexandra M. Linz ◽  
Yanjun Ma ◽  
Jose M. Perez ◽  
Kevin S. Myers ◽  
Wayne S. Kontur ◽  
...  
Keyword(s):  
Potential Range ◽  
Industrial Chemicals ◽  
Multiple Substrates ◽  
Chemically Modified ◽  
Genome Wide ◽  
Wide Range ◽  
Acid Catalyzed ◽  
Plant Polymer ◽  
Lignin Depolymerization

Lignin is a potential source of valuable chemicals, but its chemical depolymerization results in a heterogeneous mixture of aromatics and other products. Microbes could valorize depolymerized lignin by converting multiple substrates into one or a small number of products. In this study, we describe the ability of Novosphingobium aromaticivorans to metabolize 1-(4-hydroxy-3-methoxyphenyl)propane-1,2-dione (G-diketone), an aromatic Hibbert diketone which is produced during formic acid-catalyzed lignin depolymerization. By assaying genome-wide transcript levels from N. aromaticivorans during growth on G-diketone and other chemically-related aromatics, we hypothesized that the Lig dehydrogenases, previously characterized as oxidizing β-O-4 linkages in aromatic dimers, were involved in G-diketone metabolism by N. aromaticivorans . Using purified N. aromaticivorans Lig dehydrogenases, we found that LigL, LigN, and LigD each reduced the Cα ketone of G-diketone in vitro but with different substrate specificities and rates. Furthermore, LigL, but not LigN or LigD, also reduced the Cα ketone of 2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)propan-1-one (GP-1) in vitro , a derivative of G-diketone with the Cβ ketone reduced, when GP-1 was provided as a substrate. The newly identified activity of these Lig dehydrogenases expands the potential range of substrates utilized by N. aromaticivorans beyond what has been previously recognized. This is beneficial both for metabolizing a wide range of natural and non-native depolymerized lignin substrates and for engineering microbes and enzymes that are active with a broader range of aromatic compounds. Importance Lignin is a major plant polymer composed of aromatic units that have value as chemicals. However, the structure and composition of lignin has made it difficult to use this polymer as a renewable source of industrial chemicals. Bacteria like Novosphingobium aromaticivorans have the potential to make chemicals from lignin not only because of their natural ability to metabolize a variety of aromatics but also because there are established protocols to engineer N. aromaticivorans strains to funnel lignin-derived aromatics into valuable products. In this work, we report a newly discovered activity of previously characterized dehydrogenase enzymes with a chemically-modified byproduct of lignin depolymerization. We propose that the activity of N. aromaticivorans enzymes with both native lignin aromatics and those produced by chemical depolymerization will expand opportunities for producing industrial chemicals from the heterogenous components of this abundant plant polymer.

A FAMILIAL METABOLIC DISORDER WITH STORAGE OF AN UNUSUAL POLYSACCHARIDE COMPLEX

PEDIATRICS ◽  
1958 ◽  
Vol 22 (1) ◽  
pp. 20-32
Author(s):  
John M. Craig ◽  
L. Lahut Uzman
Keyword(s):  
Storage Disease ◽  
Reticuloendothelial System ◽  
Tolerance Test ◽  
Physical Development ◽  
Glycogen Storage ◽  
Storage Material ◽  
Future Studies ◽  
Histochemical Tests ◽  
Storage Cells ◽  
Glycogen Stores

A metabolic disease, characterized by the accumulation of a mixture of complex polysaccharides in liver, spleen, lung, kidney and reticuloendothelial system, is described in three patients. Its familial nature is indicated by the fact that two of the cases were siblings. The salient clinical features included hepatosplenomegaly, anemia, failure in physical development and susceptibility to respiratory infection. The disease simulates glycogen storage disease in the response in the epinephrine tolerance test, and in an inability to call on glycogen stores. Histochemical tests on the tissue containing the storage cells indicated that the material was not glycogen, even though polysaccharide in nature. The storage material was isolated from the liver of one of the cases. This isolated material proved to be a complex consisting of two major moieties. The first appeared to possess a high molecular weight, was insoluble in organic solvents, and contained glucose, galactose, glucosamine and hexuronic acids as constituents. A small amount of peptides were associated with this fraction. The second major moiety of the storage material was soluble in ethanol and contained glucose, galactose, glucosamine, fatty acids, hexuronic acids and neuraminic acid as main constituents (hence a lipopolysaccharide). Attention is drawn to the fact that the storage material would have been considered an "abnormal glycogen" if the customary procedures for the isolation of glycogen had been applied to the tissue. It is suggested that caution be exercised in future studies involving storage diseases where storage of an "abnormal glycogen" with an abnormality in side-chains is suspected.

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