Lactoferrin and hematoma detoxification after intracerebral hemorrhage

2020 ◽  
Author(s):  
Xiurong Zhao ◽  
Marian L Kruzel ◽  
Jaroslaw Aronowski
Keyword(s):  
Intracerebral Hemorrhage ◽  
Therapeutic Agent ◽  
Low Ph ◽  
Apoptotic Cells ◽  
Iron Binding ◽  
High Affinity ◽  
Iron Binding Proteins ◽  
Inflammation Resolution ◽  
Binding Glycoprotein

This review discusses the role of lactoferrin (LTF) in detoxifying hematoma after intracerebral hemorrhage (ICH). Subsequent to ICH, neutrophils enter the ICH-affected brain, where they release various granule content, including LTF. LTF is an iron-binding glycoprotein that binds Fe3+ with high affinity. Unlike other iron binding proteins, LTF can retain Fe3+ at the low pH associated with inflamed tissue. LTF’s ability to sequester Fe3+ is of particular importance to ICH pathogenesis, as large quantities of free iron, which is pro-oxidative and pro-inflammatory are generated in the ICH-affected brain due to blood hemolysis. LTF delivered to ICH-affected brain, either as therapeutic agent or through infiltrated PMNs (cells containing high levels of LTF), could benefit ICH pathogenesis. LTF is a protein with a high isoelectric point (8.7), property that enables it to binding to negatively charged apoptotic cells or proteins. Here, LTF could act as a bridging molecule that couples the apoptotic cells to LTF receptors on the cellular membranes of microglia/macrophages to facilitates the efferocytosis/erythrophagocytosis of apoptotic cells and damaged red blood cells. Thus, by virtue of sequestrating iron and facilitating efferocytosis, LTF may contribute to hematoma detoxification and hematoma/inflammation resolution after ICH.

scholarly journals Distribution of Lactoferrin Is Related with Dynamics of Neutrophils in Bacterial Infected Mice Intestine

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1496 ◽  
Author(s):  
Li Liang ◽  
Zhen-Jie Wang ◽  
Guang Ye ◽  
Xue-You Tang ◽  
Yuan-Yuan Zhang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Activity ◽  
Mucosal Immunity ◽  
Mrna Levels ◽  
Iron Binding ◽  
E Coli ◽  
New Knowledge ◽  
Activated Neutrophils ◽  
Binding Glycoprotein

Lactoferrin (Lf) is a conserved iron-binding glycoprotein with antimicrobial activity, which is present in secretions that recover mucosal sites regarded as portals of invaded pathogens. Although numerous studies have focused on exogenous Lf, little is known about its expression of endogenous Lf upon bacterial infection. In this study, we investigated the distribution of Lf in mice intestine during Escherichia coli (E. coli) K88 infection. PCR and immunohistology staining showed that mRNA levels of Lf significantly increased in duodenum, ileum and colon, but extremely decreased in jejunum at 8 h and 24 h after infection. Meanwhile, endogenous Lf was mostly located in the lamina propria of intestine villi, while Lf receptor (LfR) was in the crypts. It suggested that endogenous Lf-LfR interaction might not be implicated in the antibacterial process. In addition, it was interesting to find that the infiltration of neutrophils into intestine tissues was changed similarly to Lf expression. It indicated that the variations of Lf expression were rather due to an equilibrium between the recruitment of neutrophils and degranulation of activated neutrophils. Thus, this new knowledge will pave the way to a more effective understanding of the role of Lf in intestinal mucosal immunity.

scholarly journals Diverse Mechanisms of Antimicrobial Activities of Lactoferrins, Lactoferricins, and Other Lactoferrin-Derived Peptides

2021 ◽  
Vol 22 (20) ◽  
pp. 11264
Author(s):  
Špela Gruden ◽  
Nataša Poklar Ulrih
Keyword(s):  
Antimicrobial Activity ◽  
Amino Acid ◽  
Amino Acid Composition ◽  
Molecular Level ◽  
Antioxidant Activities ◽  
Antimicrobial Activities ◽  
Iron Binding ◽  
Primary Focus ◽  
Binding Glycoprotein

Lactoferrins are an iron-binding glycoprotein that have important protective roles in the mammalian body through their numerous functions, which include antimicrobial, antitumor, anti-inflammatory, immunomodulatory, and antioxidant activities. Among these, their antimicrobial activity has been the most studied, although the mechanism behind antimicrobial activities remains to be elucidated. Thirty years ago, the first lactoferrin-derived peptide was isolated and showed higher antimicrobial activity than the native lactoferrin lactoferricin. Since then, numerous studies have investigated the antimicrobial potencies of lactoferrins, lactoferricins, and other lactoferrin-derived peptides to better understand their antimicrobial activities at the molecular level. This review defines the current antibacterial, antiviral, antifungal, and antiparasitic activities of lactoferrins, lactoferricins, and lactoferrin-derived peptides. The primary focus is on their different mechanisms of activity against bacteria, viruses, fungi, and parasites. The role of their structure, amino-acid composition, conformation, charge, hydrophobicity, and other factors that affect their mechanisms of antimicrobial activity are also reviewed.

scholarly journals Lactoferrin: A Modulator for Immunity against Tuberculosis Related Granulomatous Pathology

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jeffrey K. Actor
Keyword(s):  
Therapeutic Efficacy ◽  
Therapeutic Agent ◽  
Iron Binding ◽  
Therapeutic Tool ◽  
Cord Factor ◽  
Pulmonary Pathology ◽  
Mucosal Secretions ◽  
Binding Glycoprotein ◽  
Promising Avenue

There is great need for a therapeutic that would limit tuberculosis related pathology and thus curtail spread of disease between individuals by establishing a “firebreak” to slow transmission. A promising avenue to increase current therapeutic efficacy may be through incorporation of adjunct components that slow or stop development of aggressive destructive pulmonary pathology. Lactoferrin, an iron-binding glycoprotein found in mucosal secretions and granules of neutrophils, is just such a potential adjunct therapeutic agent. The focus of this review is to explore the utility of lactoferrin to serve as a therapeutic tool to investigate “disruption” of the mycobacterial granuloma. Proposed concepts for mechanisms underlying lactoferrin efficacy to control immunopathology are supported by data generated based onin vivomodels using nonpathogenic trehalose 6,6′-dimycolate (TDM, cord factor).

Iron metabolism and its disorders

2010 ◽  
pp. 4386-4400
Author(s):  
T.M. Cox ◽  
John B. Porter
Keyword(s):  
Iron Metabolism ◽  
Oxygen Transport ◽  
Binding Proteins ◽  
Iron Binding ◽  
Redox States ◽  
High Affinity ◽  
Enzyme Systems ◽  
Metabolic Reactions ◽  
Iron Binding Proteins ◽  
Haem Proteins

Iron is a component of haem proteins and nonhaem enzyme systems required for oxygen transport, mitochondrial respiration, and other key metabolic reactions. The metal exists in two readily interconvertible redox states (divalent ferrous and trivalent ferric iron) that are highly reactive and toxic to tissues. High-affinity iron-binding proteins, which form stable ferric complexes, have evolved to facilitate iron transport and delivery to sites of storage and utilization, including haem biosynthesis....

scholarly journals Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall.

1996 ◽  
Vol 183 (4) ◽  
pp. 1527-1532 ◽  
Author(s):  
J Gobin ◽  
M A Horwitz
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Binding Proteins ◽  
Core Structure ◽  
Water Soluble ◽  
Side Chain ◽  
Iron Binding ◽  
Alkyl Side Chain ◽  
High Affinity ◽  
Iron Binding Proteins

To multiply and cause disease in the host, Mycobacterium tuberculosis must acquire iron from the extracellular environment at sites of replication. To do so, the bacterium releases high-affinity iron-binding siderophores called exochelins. In previous studies, we have described the purification and characterization of the exochelin family of molecules. These molecules share a common core structure with another type of high-affinity iron-binding molecule located in the cell wall of M. tuberculosis: the mycobactins. The water-soluble exochelins differ from each other and from water insoluble mycobactins in polarity, which is dependent primarily upon the length and modifications of an alkyl side chain. In this study, we have investigated the capacity of purified exochelins to remove iron from host high-affinity iron-binding molecules, and to transfer iron to mycobactins. Purified desferri-exochelins rapidly removed iron from human transferrin, whether it was 95 or 40% iron saturated, its approximate percent saturation in human serum, and from human lactoferrin. Desferri-exochelins also removed iron, but at a slower rate, from the iron storage protein ferritin. Purified ferri-exochelins, but not iron transferrin, transferred iron to desferri-mycobactins in the cell wall of live bacteria. To explore the possibility that the transfer iron from exochelins to mycobactins was influenced by their polarity, we investigated the influence of polarity on the iron affinity of exochelins. Exochelins of different polarity exchanged iron equally with each other. This study supports the concept that exochelins acquire iron for M. tuberculosis by removing this element from host iron-binding proteins and transferring it to desferri-mycobactins in the cell wall of the bacterium. The finding that ferri-exochelins but not iron transferrin transfer iron to mycobactins in the cell wall underscores the importance of exochelins in iron acquisition. This study also shows that the variable alkyl side chain on the core structure of exochelins and mycobactins, the principal determinant of their polarity, has little or no influence on their iron affinity.

scholarly journals The Mycobacterium tuberculosis High-Affinity Iron Importer, IrtA, Contains an FAD-Binding Domain

2009 ◽  
Vol 192 (3) ◽  
pp. 861-869 ◽  
Author(s):  
Michelle B. Ryndak ◽  
Shuishu Wang ◽  
Issar Smith ◽  
G. Marcela Rodriguez
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Iron Acquisition ◽  
Binding Domain ◽  
Amino Terminus ◽  
High Affinity ◽  
Iron Deficient ◽  
Essential Nutrient ◽  
Iron Binding Proteins ◽  
Fad Binding

ABSTRACT Iron is an essential nutrient not freely available to microorganisms infecting mammals. To overcome iron deficiency, bacteria have evolved various strategies including the synthesis and secretion of high-affinity iron chelators known as siderophores. The siderophores produced and secreted by Mycobacterium tuberculosis, exomycobactins, compete for iron with host iron-binding proteins and, together with the iron-regulated ABC transporter IrtAB, are required for the survival of M. tuberculosis in iron deficient conditions and for normal replication in macrophages and in mice. This study further characterizes the role of IrtAB in M. tuberculosis iron acquisition. Our results demonstrate a role for IrtAB in iron import and show that the amino terminus domain of IrtA is a flavin-adenine dinucleotide-binding domain essential for iron acquisition. These results suggest a model in which the amino terminus of IrtA functions to couple iron transport and assimilation.

scholarly journals The role of apoptosis during inflammation resolution in Lyme arthritis

2019 ◽  
Author(s):  
◽  
Kinsey Alyss Hilliard
Keyword(s):  
Ppar Gamma ◽  
Lyme Arthritis ◽  
Apoptotic Cells ◽  
Cellular Infiltrate ◽  
Free Treatment ◽  
C3h Mice ◽  
A Cell ◽  
Inflammation Resolution ◽  
Disc Formation

Experimental Lyme arthritis is induced by the infection of C3H mice with the spirochete, Borrelia burgdorferi, and is a valuable model to study the regulation of inflammation during bacterial infection. While the lab has previously focused on how inflammation is initiated, this thesis focuses on the role of apoptotic cells during inflammation resolution in Lyme arthritis. We show administration of apoptotic cells can be used to initiate earlier resolution in B. burgdorferi-infected mice by decreased neutrophil recruitment, and this may be due to increased PPAR-[gamma] activation. Additionally, the PPAR-[gamma] agonist, rosiglitazone, can be used as a cell-free treatment to elicit a similar effect as the apoptotic cells. We also define the role of various eicosanoids during inflammation resolution. If apoptosis or efferocytosis, the phagocytosis of apoptotic cells, is dysregulated, it can cause exacerbated inflammation and arthritis. BLT1-/- neutrophils have a defect in apoptosis and efferocytosis recognition to due decreased DISC formation. This is a result of increased cAMP in BLT1-/- neutrophils due to the inability for LTB4/BLT1 signaling to downregulate cAMP. Additionally, macrophages must be able to produce PGE2 to be affected by and efferocytose apoptotic cells efficiently. Deficiencies in either of these eicosanoid signaling pathways results in increased cellular infiltrate during arthritis resolution, prolonging inflammation. We also show apoptotic cells actively secrete mediators to aid in their alteration of the inflammatory response. These results demonstrate the importance of apoptosis and efferocytosis during inflammation resolution in Lyme arthritis and several mechanisms involved.

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