scholarly journals Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1997 ◽  
Author(s):  
Romina Mancinelli ◽  
Luigi Rosa ◽  
Antimo Cutone ◽  
Maria Stefania Lepanto ◽  
Antonio Franchitto ◽  
...  
Keyword(s):  
Viral Hepatitis ◽  
Viral Entry ◽  
Iron Homeostasis ◽  
Iron Chelation ◽  
Host Cells ◽  
Surface Receptors ◽  
Inflammatory Processes ◽  
Related Proteins ◽  
Binding Glycoprotein

The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes’ iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined.

scholarly journals Lactoferrin Against SARS-CoV-2: In Vitro and In Silico Evidences

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Campione ◽  
Caterina Lanna ◽  
Terenzio Cosio ◽  
Luigi Rosa ◽  
Maria Pia Conte ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
In Silico ◽  
Iron Homeostasis ◽  
Host Cells ◽  
Intracellular Iron ◽  
Infection And Inflammation ◽  
Direct Recognition

Lactoferrin (Lf) is a cationic glycoprotein synthetized by exocrine glands and is present in all human secretions. It is also secreted by neutrophils in infection and inflammation sites. This glycoprotein possesses antimicrobial activity due to its capability to chelate two ferric ions per molecule, as well as to interact with bacterial and viral anionic surface components. The cationic features of Lf bind to cells, protecting the host from bacterial and viral injuries. Its anti-inflammatory activity is mediated by the ability to enter inside the nucleus of host cells, thus inhibiting the synthesis of proinflammatory cytokine genes. In particular, Lf down-regulates the synthesis of IL-6, which is involved in iron homeostasis disorders and leads to intracellular iron overload, favoring viral replication and infection. The well-known antiviral activity of Lf has been demonstrated against DNA, RNA, and enveloped and naked viruses and, therefore, Lf could be efficient in counteracting also SARS-CoV-2 infection. For this purpose, we performed in vitro assays, proving that Lf exerts an antiviral activity against SARS-COV-2 through direct attachment to both SARS-CoV-2 and cell surface components. This activity varied according to concentration (100/500 μg/ml), multiplicity of infection (0.1/0.01), and cell type (Vero E6/Caco-2 cells). Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between Lf and the spike S glycoprotein, which can thus hinder viral entry into the cells. These in vitro observations led us to speculate a potential supplementary role of Lf in the management of COVID-19 patients.

Plasminogen: an enigmatic zymogen

Blood ◽  
2021 ◽  
Author(s):  
Charithani B Keragala ◽  
Robert L Medcalf
Keyword(s):  
Animal Studies ◽  
Wound Repair ◽  
Active Form ◽  
Cell Behaviour ◽  
Surface Receptors ◽  
Enzymatic Cascades ◽  
Inflammatory Processes ◽  
Over 40 Years

Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. The therapeutic targeting of the fibrinolytic system to date has been for two purposes: to promote plasmin generation for thromboembolic conditions, or to stop plasmin to reduce bleeding. However, both plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for over 40 years, the anti-fibrinolytic agent, tranexamic acid, has been administered for its serendipitously discovered skin whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades including complement. In addition, plasminogen, via binding to one of its dozen cell-surface receptors, can modulate cell behaviour and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. While many of these more recent findings have been derived from in vitro or animal studies, the use of anti-fibrinolytics to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its haemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that anti-fibrinolytic agents may have anti-viral benefits. Here we review the broadening role of the plasminogen activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and haemostasis.

scholarly journals From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 705 ◽  
Author(s):  
Emilie Picard ◽  
Alejandra Daruich ◽  
Jenny Youale ◽  
Yves Courtois ◽  
Francine Behar-Cohen
Keyword(s):  
Electron Transfer ◽  
Iron Homeostasis ◽  
Iron Chelation ◽  
Retinal Diseases ◽  
Iron Binding ◽  
Vital Functions ◽  
Iron Binding Protein ◽  
And Function ◽  
Organ Dysfunctions

Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe2+ to Fe3+ involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review is to illustrate the primordial role of iron and local iron homeostasis in retinal physiology and vision, as well as the pathological consequences of iron excess in animal models of retinal degeneration and in human retinal diseases. We summarize evidence of the potential therapeutic effect of iron chelation in retinal diseases and especially the interest of transferrin, a ubiquitous endogenous iron-binding protein, having the ability to treat or delay degenerative retinal diseases.

scholarly journals 0790 The Clinical Significance of Hepcidin as a Predictive Value for Treatment Responses in Restless Legs Syndrome

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A300-A301
Author(s):  
H Im
Keyword(s):  
Restless Legs Syndrome ◽  
Iron Homeostasis ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Restless Legs ◽  
Inflammatory Processes ◽  
Drug Naïve ◽  
Therapeutic Responses

Abstract Introduction Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is related to iron-dopamine dysregulation and immune system alteration. Hepcidin is the key regulatory hormone of systemic iron homeostasis and is related to inflammatory processes. We aimed to evaluate the clinical utility of hepcidin as a diagnostic biomarker and index of therapeutic responses in RLS patients after dopaminergic treatment. Methods Non-anemic and drug-naive RLS patients (n=18) and healthy controls (n=15) were enrolled. Hepcidin (pre-prohepcidin) and iron-related values in serum were measured upon the first visit in both groups and 12 weeks later after dopaminergic treatment in 12 RLS patients. Information about sociodemographic characteristics, sleep-related profiles, mood, and anxiety was obtained upon the first visit in all participants as well as after treatment in RLS patients. Results Hepcidin levels exhibited no significant differences between patients with drug-naïve RLS and healthy controls at a diagnosis (7.1 ± 2.4 vs. 7.0 ± 3.2 ng/ml, p = 0.978). Decreased hepcidin levels were significantly associated with decreased RLS severity (β = 0.002, 95% CI = 0.00−0.00, p = 0.005) and improved quality of life (β = 0.002, 95% CI = 0.00−7.01, p = 0.044) in a dose-dependent manner after 12 weeks of treatment with a dopamine agonist. This association was independent of age, sex, inflammatory markers, sleep quality, insomnia, daytime sleepiness, depression, and anxiety. Conclusion This study demonstrates a role of hepcidin as a predictor of therapeutic responses in RLS patients. Support This work was supported by the Korea Health technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, South Korea [grant number HI17C2072].

scholarly journals Perspectives and Challenges in the Fight Against COVID-19: The Role of Genetic Variability

2021 ◽  
Vol 11 ◽  
Author(s):  
Mariana Guilger-Casagrande ◽  
Cecilia T. de Barros ◽  
Vitória A. N. Antunes ◽  
Daniele R. de Araujo ◽  
Renata Lima
Keyword(s):  
Disease Severity ◽  
Viral Entry ◽  
Expression Profiles ◽  
Clinical Signs ◽  
Pharmacological Therapy ◽  
Genetic Features ◽  
Inflammatory Processes ◽  
Clinical Responses ◽  
Infection Mechanisms

In the last year, the advent of the COVID-19 pandemic brought a new consideration for the multidisciplinary sciences. The unknown mechanisms of infection used by SARS-CoV-2 and the absence of effective antiviral pharmacological therapy, diagnosis methods, and vaccines evoked scientific efforts on the COVID-19 outcome. In general, COVID-19 clinical features are a result of local and systemic inflammatory processes that are enhanced by some preexistent comorbidities, such as diabetes, obesity, cardiovascular, and pulmonary diseases, and biological factors, like gender and age. However, the discrepancies in COVID-19 clinical signs observed among those patients lead to investigations about the critical factors that deeply influence disease severity and death. Herein, we present the viral infection mechanisms and its consequences after blocking the angiotensin-converting enzyme 2 (ACE2) axis in different tissues and the progression of inflammatory and immunological reactions, especially the influence of genetic features on those differential clinical responses. Furthermore, we discuss the role of genotype as an essential indicator of COVID-19 susceptibility, considering the expression profiles, polymorphisms, gene identification, and epigenetic modifications of viral entry factors and their recognition, as well as the infection effects on cell signaling molecule expression, which amplifies disease severity.

scholarly journals Cathepsins: innate immune proteases that regulate viral entry into host cells

2018 ◽  
Vol 72 ◽  
pp. 253-263 ◽  
Author(s):  
Magdalena Bossowska-Nowicka ◽  
Felix N. Toka ◽  
Matylda Mielcarska ◽  
Lidia Szulc-Dąbrowska
Keyword(s):  
Viral Entry ◽  
Antigen Processing ◽  
Viral Infections ◽  
Innate Immune ◽  
Host Cells ◽  
Human Pathogens ◽  
Cellular Mechanisms ◽  
Cathepsin Proteases ◽  
Cell Adhesion And Migration

Cathepsins are group of endolysosomal proteases that regulate the mechanisms of innate and adaptive immunity, including cell adhesion and migration, antigen processing and presentation and resistance to several viral infections. Some cathepsins are required for Toll-like receptor (TLR)3, TLR7 and TLR9 cleavage and the formation of functional receptors that participate in sensing viral nucleic acids. Moreover, cathepsins directly stimulate or inhibit cytokine secretion involved in the regulation of antiviral innate immune response. Recent findings underline the important role of cathepsins in the entry of filoviruses, reoviruses, retroviruses and other types of viruses into the host cell. Many enveloped viruses require the presence of cathepsins for efficient fusion with membranes of infected cells, and the inhibition of their activity results in a significant reduction of virus replication. In addition, many viruses utilize conserved cellular mechanisms, such as endocytosis or low pH within the endosome, for efficient penetration into the cell interior, disassembly of viral capsid, and other stages of productive viral replication cycle. Therefore, a better understanding of the functional role of cathepsin proteases in the pathogenesis of viral infections should lead to the development of novel therapeutics for a variety of particularly dangerous human pathogens.

scholarly journals Ebola Virus Requires Phosphatidylserine Scrambling Activity for Efficient Budding and Optimal Infectivity

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 35
Author(s):  
Marissa Acciani ◽  
Maria Lay ◽  
Katherine E. Havranek ◽  
Avery Duncan ◽  
Hersha Iyer ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Apoptotic Cell ◽  
Viral Envelope ◽  
Host Cells ◽  
Surface Receptors ◽  
Outer Leaflet ◽  
Virus Like Particle ◽  
Vesicular Stomatitis ◽  
Virion Surface

Ebola virus (EBOV) interacts with cells using multiple categories of cell-surface receptors, including C-type lectins and phosphatidylserine (PS) receptors. PS receptors typically bind to apoptotic cell membrane PS and orchestrate the uptake and clearance of apoptotic bodies. Many viruses coated with PS-containing lipid envelopes, acquired during budding from host cells, can also exploit these receptors for internalization. PS is restricted to the inner leaflet of the plasma membrane in homeostatic cells, an orientation that would be unfavorable for PS receptor-mediated uptake if conserved on the viral envelope. Therefore, it is theorized that viral infection induces host-cell PS externalization to the outer leaflet during replication. Cells have several membrane scramblase enzymes that enrich outer leaflet PS when activated. Here, we investigate the role of two scramblases, TMEM16F and XKR8, as possible mediators of cellular and viral envelope surface PS levels during recombinant vesicular stomatitis virus (VSV) in which the VSV glycoprotein was replaced with the Ebola glycoprotein (rVSV/EBOV-GP) replication and EBOV virus-like particle (VLP) production. We find that rVSV/EBOV-GP and EBOV VLPs produced in XKR8 knockout cells contain two- to threefold less PS in their outer leaflets. Consequently, rVSV/EBOV-GP produced in deltaXKR8 is 70% less efficient at infecting cells through apoptotic mimicry as compared to the viruses produced by parental cells. In addition, the budding efficiency of both recombinant VSV particles and VLPs was significantly reduced in cells lacking XKR8. Our data suggest that virion surface PS acquisition requires XKR8 activity, whereas the deletion of TMEM16F did not affect EBOV-GP-mediated entry of VLP production. Unexpectedly, we observed an additional role of XKR8 in rVSV/G, rVSV/EBOV-GP, and EBOV VLP budding.

Abstract 12928: Vascular Complications in Covid-19 and Role of Zinc in Viral Inhibition

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Donghui Zhu ◽  
Zhen Zhao
Keyword(s):  
Viral Entry ◽  
Vascular Complications ◽  
Functional Change ◽  
Cell Entry ◽  
Host Cells ◽  
Binding Motif ◽  
Vascular Cells ◽  
Viral Inhibition ◽  
S Protein

Although COVID-19 is associated with severe respiratory dysfunctions, conspicuous vascular complications and neurological manifestations have been reported worldwide. Of note, two distinctive features have been noticed in severe patients, progressive increase of inflammation and an unusual trend of hypercoagulation. Interestingly, evidence is mounting that healthy blood vessels protect children from serious effects of COVID-19, such as stroke. These findings suggest vascular complications play a key role in the progress of COVID-19, warranting an investigation to its pathophysiology and treatment strategy related to vascular cells. Cell entry of this SARS-CoV-2 virus depends on binding of the viral spike (S) proteins to cellular receptor ACE2, which could be a key target for blocking the viral entry into host cells. ACE2 is a zinc (Zn) binding metallopeptidase while Zn possesses distinct antiviral properties against many human viruses including coronaviruses. Although the mechanistic studies are lacking, Zn appears to inhibit viral protease and polymerase enzymatic processes, and physical processes such as virus attachment, cell entry, and uncoating. In fact, our data showed that ACE2 has multiple affinity binding sites for Zn. Excess bindings of ionic Zn to ACE2 led to its conformational or functional change, therefore, interfering with its ability to metabolize its substrate as well as inhibiting its binding to S protein. Computational modeling also revealed that one critical Zn binding motif is located in ACE2’s binding domain to S protein, and docking affinity of S protein to ACE2 was significantly reduced after Zn binding to this specific site. Moreover, cell and animal studies using pseudo-virus bearing CoV-2-S protein validated that significantly lower infection of vascular cells in the presence of Zn was observed. Thus, targeting vascular complications in COVID-19 may offer strong benefits including the potential therapeutic role of Zn.

scholarly journals Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

2020 ◽  
Vol 21 (5) ◽  
pp. 1676 ◽  
Author(s):  
James Elste ◽  
Dominik Kaltenbach ◽  
Vraj R. Patel ◽  
Max T. Nguyen ◽  
Harsh Sharthiya ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Small Molecule ◽  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Host Cells ◽  
Early Gene ◽  
Surface Receptors ◽  
Viral Spread ◽  
Multiple Receptors ◽  
Life Threatening

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a ‘poly-pharmacy’ approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

scholarly journals Iron and Neurodegeneration in Multiple Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Michael Khalil ◽  
Charlotte Teunissen ◽  
Christian Langkammer
Keyword(s):  
Multiple Sclerosis ◽  
Iron Homeostasis ◽  
Venous Insufficiency ◽  
Quantitative Mri ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Etiologic Role ◽  
Quantitative Manner ◽  
Related Proteins

Increased iron deposition might be implicated in multiple sclerosis (MS). Recent development of MRI enabled to determine brain iron levels in a quantitative manner, which has put more interest on studying the role of iron in MS. Evidence for abnormal iron homeostasis in MS comes also from analyses of iron and iron-related proteins in CSF and blood and postmortem MS brain sections. However, it is not yet clear if iron accumulation is implicated in MS pathology or merely reflects an epiphenomenon. Further interest has been generated by the idea of chronic cerebrospinal venous insufficiency that might be associated with brain iron accumulation due to a reduction in venous outflow, but its existence and etiologic role in MS are currently controversially debated. In future studies, combined approaches applying quantitative MRI together with CSF and serum analyses of iron and iron-related proteins in a clinical followup setting might help to elucidate the implication of iron accumulation in MS.

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