scholarly journals Targeting Host Glycolysis as a Strategy for Antimalarial Development

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrew J. Jezewski ◽  
Yu-Hsi Lin ◽  
Julie A. Reisz ◽  
Rachel Culp-Hill ◽  
Yasaman Barekatain ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Redox Balance ◽  
Parasite Growth ◽  
Red Cell ◽  
Cell Toxicity ◽  
Microbial Diseases ◽  
Cellular Energy ◽  
Cellular Effects ◽  
Disease States ◽  
Treatment Of Obesity

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth.

scholarly journals Accelerated erythrocyte senescence causes dose-limiting anemia of antimalarial enolase inhibitors

2020 ◽  
Author(s):  
Andrew J. Jezewski ◽  
Yu-Hsi Lin ◽  
Julie A. Reisz ◽  
Rachel Culp-Hill ◽  
Yasaman Barekatain ◽  
...  
Keyword(s):  
Blood Cell ◽  
Therapeutic Strategy ◽  
Redox Balance ◽  
Red Cell ◽  
Cell Toxicity ◽  
Microbial Diseases ◽  
Cellular Energy ◽  
Cellular Effects ◽  
Disease States ◽  
Specific Inhibitors

SUMMARYGlycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are being investigated for obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a key dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage that induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity.

scholarly journals Methyldopa: Physicochemical Characterization of the Erythrocyte Autoantibody

Blood ◽  
1973 ◽  
Vol 42 (2) ◽  
pp. 247-255 ◽  
Author(s):  
Barry Wenz ◽  
Parviz Lalezari
Keyword(s):  
Temperature Gradient ◽  
Lupus Erythematosus ◽  
Physicochemical Characterization ◽  
Red Cell ◽  
Disease States ◽  
Graphic Data ◽  
Cell Antibody ◽  
Dissociation Curves ◽  
Antigen Antibody

Abstract A modification of the Polybrene technique for red blood cell antibody characterization has been employed to differentiate the panhemagglutinins arising during methyldopa administration from those accompanying other disease states. Dissociation characteristics of methyldopa-associated antigen-antibody complexes were determined by temperature gradient dissociation technique. Data obtained by this technique for cell-bound antibody were found to distinguish this antibody from those accompanying systemic lupus erythematosus (SLE) and Pronestyl therapy. Graphic data derived from temperature gradient dissociation curves at varying antibody concentrations were obtained for the methyldopa-induced serum antibodies. Results obtained with samples from all six patients were found to be relatively uniform in relation to each other, and different from similarly derived results for red cell antibodies accompanying idiopathic autoimmune hemolytic anemia and Hodgkin’s disease. By means of these procedures, as well as standard blood banking techniques, distinguishing features are described that permit in vitro segregation of these distinct groups of red cell autoantibodies.

scholarly journals Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Tamara Mirzapoiazova ◽  
Frances E. Lennon ◽  
Bolot Mambetsariev ◽  
Michael Allen ◽  
Jacob Riehm ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Extracellular Vesicles ◽  
Therapeutic Strategy ◽  
Extracellular Vesicle ◽  
The Body ◽  
Vascular Integrity ◽  
Barrier Disruption ◽  
Disease States ◽  
Barrier Regulation

Defects in vascular integrity are an initiating factor in several disease processes. We have previously reported that high molecular weight hyaluronan (HMW-HA), a major glycosaminoglycan in the body, promotes rapid signal transduction in human pulmonary microvascular endothelial cells (HPMVEC) leading to barrier enhancement. In contrast, low molecular weight hyaluronan (LMW-HA), produced in disease states by hyaluronidases and reactive oxygen species (ROS), induces HPMVEC barrier disruption. However, the mechanism(s) of sustained barrier regulation by HA are poorly defined. Our results indicate that long-term (6–24 hours) exposure of HMW-HA induced release of a novel type of extracellular vesicle from HLMVEC called enlargeosomes (characterized by AHNAK expression) while LMW-HA long-term exposure promoted release of exosomes (characterized by CD9, CD63, and CD81 expression). These effects were blocked by inhibiting caveolin-enriched microdomain (CEM) formation. Further, inhibiting enlargeosome release by annexin II siRNA attenuated the sustained barrier enhancing effects of HMW-HA. Finally, exposure of isolated enlargeosomes to HPMVEC monolayers generated barrier enhancement while exosomes led to barrier disruption. Taken together, these results suggest that differential release of extracellular vesicles from CEM modulate the sustained HPMVEC barrier regulation by HMW-HA and LMW-HA. HMW-HA-induced specialized enlargeosomes can be a potential therapeutic strategy for diseases involving impaired vascular integrity.

scholarly journals Red cell membrane: past, present, and future

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 3939-3948 ◽  
Author(s):  
Narla Mohandas ◽  
Patrick G. Gallagher
Keyword(s):  
Cell Membrane ◽  
Functional Characterization ◽  
Cell Types ◽  
Red Cell ◽  
Exciting Field ◽  
Inherited Disorders ◽  
Red Cell Membrane ◽  
Membrane Function ◽  
Disease States ◽  
The Many

Abstract As a result of natural selection driven by severe forms of malaria, 1 in 6 humans in the world, more than 1 billion people, are affected by red cell abnormalities, making them the most common of the inherited disorders. The non-nucleated red cell is unique among human cell type in that the plasma membrane, its only structural component, accounts for all of its diverse antigenic, transport, and mechanical characteristics. Our current concept of the red cell membrane envisions it as a composite structure in which a membrane envelope composed of cholesterol and phospholipids is secured to an elastic network of skeletal proteins via transmembrane proteins. Structural and functional characterization of the many constituents of the red cell membrane, in conjunction with biophysical and physiologic studies, has led to detailed description of the way in which the remarkable mechanical properties and other important characteristics of the red cells arise, and of the manner in which they fail in disease states. Current studies in this very active and exciting field are continuing to produce new and unexpected revelations on the function of the red cell membrane and thus of the cell in health and disease, and shed new light on membrane function in other diverse cell types.

scholarly journals pH Dependent Hemolytic Systems. III. The Physical Properties of the Serum Factors Involved, with Some Observations on Their Occurrence in Various Disease States in Man

Blood ◽  
1961 ◽  
Vol 18 (3) ◽  
pp. 349-363 ◽  
Author(s):  
STANLEY YACHNIN ◽  
FRANK H. GARDNER
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Red Cells ◽  
Red Cell ◽  
Serum Factors ◽  
Disease States ◽  
Large Size ◽  
Serum Fractions ◽  
Ph Dependent ◽  
Sulfhydryl Compounds

Abstract Agglutinins for various artificially altered red blood cells belong to the class of 19S macroglobulins, which migrate electrophoretically as fast gamma or slow beta globulins. The agglutinin activity of serum for altered red cells is readily destroyed by sulfhydryl compounds. Hemolysins for altered red cells are not readily recoverable from serum fractions prepared by starch block electrophoresis or density gradient ultracentrifugation, but, when present, are found to have the same properties. This information lends credence to the concept of these serum factors as examples of "natural antibody," although the stimulus to their formation is not understood. The sera from patients with various types of hemolytic anemias and various dysproteinemias including macroglobulinemia were found to contain normal amounts of altered red cell agglutinins and hemolysins. The sera from three patients with congenital agammaglobulinemia were studied. Two of these sera contained agglutinins and hemolysins for altered red blood cells, as well as isohemolysins and isoagglutinins. The significance of this finding is discussed. The "T" agglutinin and the agglutinin for periodate-treated red cells, both of which are macroglobulins, have been shown by other workers to be absent from newborn sera. Their inability to cross the placenta can be explained by their large size.

scholarly journals Two Faces of Vitamin C—Antioxidative and Pro-Oxidative Agent

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1501
Author(s):  
Julia Kaźmierczak-Barańska ◽  
Karolina Boguszewska ◽  
Angelika Adamus-Grabicka ◽  
Bolesław T. Karwowski
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Vitamin C ◽  
Oxidative Dna Damage ◽  
Redox Balance ◽  
Cellular Effects ◽  
Vitamin C Supplementation ◽  
The Central Nervous System ◽  
Radioprotective Properties

Vitamin C has been known for decades. It is common in everyday use as an element of the diet, supplementation, and a preservative. For years, research has been conducted to precisely determine the mechanism of action of ascorbate in the cell. Available results indicate its multi-directional cellular effects. Vitamin C, which belongs to antioxidants scavenging free radicals, also has a ‘second face’—as a pro-oxidative factor. However, whether is the latter nature a defect harmful to the cell, or whether a virtue that is a source of benefit? In this review, we discuss the effects of vitamin C treatment in cancer prevention and the role of ascorbate in maintaining redox balance in the central nervous system (CNS). Finally, we discuss the effect of vitamin C supplementation on biomarkers of oxidative DNA damage and review the evidence that vitamin C has radioprotective properties.

scholarly journals Erythrokinetics: Quantitative Measurements of Red Cell Production and Destruction in Normal Subjects and Patients with Anemia

Blood ◽  
1956 ◽  
Vol 11 (4) ◽  
pp. 291-309 ◽  
Author(s):  
ELOISE R. GIBLETT ◽  
DANIEL H. COLEMAN ◽  
GIACOMO PIRZIO-BIROLI ◽  
DENNIS M. DONOHUE ◽  
ARNO G. MOTULSKY ◽  
...  
Keyword(s):  
Cell Mass ◽  
Normal Subjects ◽  
Red Cells ◽  
Red Cell ◽  
Chronic Anemia ◽  
Cell Production ◽  
Plasma Iron ◽  
Disease States ◽  
Quantitative Measurements ◽  
Normal Ratio

Abstract Red cell turnover of 19 normal subjects and 25 anemic patients was measured with the following technique: erythroid-myeloid ratio of the marrow, reticulocyte counts, plasma iron turnover, red cell utilization of radioiron, and urobilinogen determinations. Measurements of blood production and destruction were so expressed as to allow comparison between normal and anemic individuals of different size and different red cell mass. The usefulness and disadvantages of each procedure in the study of anemia are discussed. From studies of various types of anemia, it has become apparent that erythropoiesis must be defined in terms of total quantity of red cells produced and in terms of the portion of red cells produced in the marrow which are delivered to the circulating blood (effective versus ineffective erythropoiesis). A quantitative defect alone exists when a normal ratio is maintained between effective and total erythropoiesis. Here, there are changes of similar magnitude of all erythrokinetic indices, although reticulocyte and urobilinogen values are occasionally disproportionately high. The normal marrow appears to be able to increase its effective red cell production to three times normal in acute anemia and six times normal in chronic anemia. In many disease states this maximal quantitative response is impaired. Dyspoiesis of the marrow is characterized by a dissociation of erythrokinetic indices. Values which reflect total erythropoiesis (i.e., plasma iron turnover, fecal urobilinogen and erythroid-myeloid ratio of the marrow) are considerably greater than the reticulocyte level and red cell utilization of radioiron which represent effective erythropoiesis. Such defects may result in the pattern of a hemolytic process or aregenerative anemia, depending on their severity.

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