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Lactoferrin, the Moonlighting Protein of Innate Immunity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 14745

Special Issue Editors


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Guest Editor
Dipartimento di Scienze biochimiche ‘A. Rossi Fanelli’, Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: iron; copper; multicopper oxidase; ceruloplasmin; ferroportin; lactoferrin; neurodegeneration; oxidative stress; yeast; membrane proteins
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Guest Editor
Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
Interests: lactoferrin; iron homeostasis; iron-proteins; inflammation; oxidative stress; ferroportin; yeast; membrane proteins
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
Interests: iron homeostasis; ceruloplasmin; ferroportin; copper; metalloproteins; lactoferrin; inflammation; structural biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lactoferrin (Lf), a natural glycoprotein of the innate immunity, is becoming more and more attractive for researchers from different fields due to its multiple functions and applications. Beyond its initially discovered antimicrobial effects, Lf is currently recognised as a potent multi-targeting nutraceutical, endowed with immunomodulatory, anti-inflammatory, anti-oxidant and anti-cancer properties. Of note, Lf shows a wide range of tolerability, being classified as a “generally recognized as safe” (GRAS) substance by the USA Food and Drug Administration. At mechanistic level, some of the functions exerted by Lf have been related to both its iron-binding ability and its highly cationic charge. However, most of its biological effects still need to be fully appreciated and unveiled. Moreover, Lf is recently emerging as a powerful carrier for the delivery of biologically active nanoparticles.

This Special Issue is focused on investigating new structural and functional properties of Lf from different species, including bovine Lf, which has mostly been applied in in vitro, in vivo and clinical studies. Areas to be covered may include but are not limited to the relation between molecular structure and function, interaction with other proteins, regulation of intracellular pathways, development of new technologies aimed to improve its bioavailability, applications as scaffold for nanoparticle delivery. Original papers and review articles on these and related topics are welcome.

Dr. Maria Carmela Bonaccorsi Di Patti
Prof. Antimo Cutone
Prof. Giovanni Musci
Guest Editors

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Keywords

  • lactoferrin
  • iron
  • nutraceutical
  • nanocarrier
  • inflammation

Published Papers (6 papers)

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Editorial

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4 pages, 222 KiB  
Editorial
Lactoferrin, the Moonlighting Protein of Innate Immunity
by Antimo Cutone, Giovanni Musci and Maria Carmela Bonaccorsi di Patti
Int. J. Mol. Sci. 2023, 24(21), 15888; https://doi.org/10.3390/ijms242115888 - 2 Nov 2023
Cited by 1 | Viewed by 1179
Abstract
Lactoferrin (Lf), a naturally occurring glycoprotein involved in innate immunity, was first discovered in bovine milk [...] Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)

Research

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20 pages, 6218 KiB  
Article
Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat
by Giusi Ianiro, Veronica D’Ezio, Ludovica Carpinelli, Cecilia Casella, Maria Carmela Bonaccorsi di Patti, Luigi Rosa, Piera Valenti, Marco Colasanti, Giovanni Musci, Antimo Cutone and Tiziana Persichini
Int. J. Mol. Sci. 2023, 24(9), 7947; https://doi.org/10.3390/ijms24097947 - 27 Apr 2023
Cited by 4 | Viewed by 1940
Abstract
The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc [...] Read more.
The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc cystine/glutamate antiporter which, in turn, can trigger glutamate-mediated excitotoxicity. Here, we present data on the efficacy of bovine Lactoferrin (bLf), both in its native (Nat-bLf) and iron-saturated (Holo-bLf) forms, in counteracting oxidative stress in U373 human astroglial cells constitutively expressing the viral protein (U373-Tat). Our results show that, dependent on iron saturation, both Nat-bLf and Holo-bLf can boost host antioxidant response by up-regulating System Xc and the cell iron exporter Ferroportin via the Nuclear factor erythroid 2-related factor (Nrf2) pathway, thus reducing Reactive Oxygen Species (ROS)-mediated lipid peroxidation and DNA damage in astrocytes. In U373-Tat cells, both forms of bLf restore the physiological internalization of Transferrin (Tf) Receptor 1, the molecular gate for Tf-bound iron uptake. The involvement of astrocytic antioxidant response in Tat-mediated neurotoxicity was evaluated in co-cultures of U373-Tat with human neuronal SH-SY5Y cells. The results show that the Holo-bLf exacerbates Tat-induced excitotoxicity on SH-SY5Y, which is directly dependent on System-Xc upregulation, thus highlighting the mechanistic role of iron in the biological activities of the glycoprotein. Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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11 pages, 1291 KiB  
Article
Myopia Is Suppressed by Digested Lactoferrin or Holo-Lactoferrin Administration
by Yifan Liang, Shin-ichi Ikeda, Junhan Chen, Yan Zhang, Kazuno Negishi, Kazuo Tsubota and Toshihide Kurihara
Int. J. Mol. Sci. 2023, 24(6), 5815; https://doi.org/10.3390/ijms24065815 - 18 Mar 2023
Cited by 3 | Viewed by 1953
Abstract
Myopia is becoming a leading cause of vision impairment. An effective intervention is needed. Lactoferrin (LF) is a protein that has been reported to inhibit myopia progression when taken orally. This study looked at the effects of different forms of LF, such as [...] Read more.
Myopia is becoming a leading cause of vision impairment. An effective intervention is needed. Lactoferrin (LF) is a protein that has been reported to inhibit myopia progression when taken orally. This study looked at the effects of different forms of LF, such as native LF and digested LF, on myopia in mice. Mice were given different forms of LF from 3 weeks of age, and myopia was induced with minus lenses from 4 weeks of age. Results showed that mice given digested LF or holo-LF had a less elongated axial length and thinned choroid, compared to those given native-LF. Gene expression analysis also showed that the groups given native-LF and its derivatives had lower levels of certain cytokines and growth factors associated with myopia. These results suggest that myopia can be more effectively suppressed by digested LF or holo-LF than native-LF. Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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18 pages, 3000 KiB  
Article
Lactoferrin Alleviates Lipopolysaccharide-Induced Infantile Intestinal Immune Barrier Damage by Regulating an ELAVL1-Related Signaling Pathway
by Chaonan Li, Xinkui Liu, Zhihong Huang, Yiyan Zhai, Huiying Li and Jiarui Wu
Int. J. Mol. Sci. 2022, 23(22), 13719; https://doi.org/10.3390/ijms232213719 - 8 Nov 2022
Cited by 5 | Viewed by 1842
Abstract
As the most important intestinal mucosal barrier of the main body, the innate immune barrier in intestinal tract plays especially pivotal roles in the overall health conditions of infants and young children; therefore, how to strengthen the innate immune barrier is pivotal. A [...] Read more.
As the most important intestinal mucosal barrier of the main body, the innate immune barrier in intestinal tract plays especially pivotal roles in the overall health conditions of infants and young children; therefore, how to strengthen the innate immune barrier is pivotal. A variety of bioactivities of lactoferrin (LF) has been widely proved, including alleviating enteritis and inhibiting colon cancer; however, the effects of LF on intestinal immune barrier in infants and young children are still unclear, and the specific mechanism on how LF inhibits infantile enteritis by regulating immune signaling pathways is unrevealed. In the present study, we firstly performed pharmacokinetic analyses of LF in mice intestinal tissues, stomach tissues and blood, through different administration methods, to confirm the metabolic method of LF in mammals. Then we constructed in Vitro and in Vivo infantile intestinal immune barrier damage models utilizing lipopolysaccharide (LPS), and evaluated the effects of LF in alleviating LPS-induced intestinal immune barrier damage. Next, the related immune molecular mechanism on how LF exerted protective effects was investigated, through RNA-seq analyses of the mouse primary intestinal epithelial cells, and the specific genes were analyzed and screened out. Finally, the genes and their related immune pathway were validated in mRNA and protein levels; the portions of special immune cells (CD4+ T cells and CD8+ T cells) were also detected to further support our experimental results. Pharmacokinetic analyses demonstrated that the integrity of LF could reach mice stomach and intestine after oral gavage within 12 h, and the proper administration of LF should be the oral route. LF was proven to down–regulate the expression levels of inflammatory cytokines in both the primary intestinal epithelial cells and mice blood, especially LF without iron (Apo-LF), indicating LF alleviated infantile intestinal immune barrier damage induced by LPS. And through RNA-seq analyses of the mouse primary intestinal epithelial cells treated with LPS and LF, embryonic lethal abnormal vision Drosophila 1 (ELAVL1) was selected as one of the key genes, then the ELAVL1/PI3K/NF-κB pathway regulated by LF was verified to participate in the protection of infantile intestinal immune barrier damage in our study. Additionally, the ratio of blood CD4+/CD8+ T cells was significantly higher in the LF-treated mice than in the control mice, indicating that LF distinctly reinforced the overall immunity of infantile mice, further validating the strengthening bioactivity of LF on infantile intestinal immune barrier. In summary, LF was proven to alleviate LPS-induced intestinal immune barrier damage in young mice through regulating ELAVL1-related immune signaling pathways, which would expand current knowledge of the functions of bioactive proteins in foods within different research layers, as well as benefit preclinical and clinical researches in a long run. Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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12 pages, 1802 KiB  
Article
Lactoferrin Inhibition of the Complex Formation between ACE2 Receptor and SARS CoV-2 Recognition Binding Domain
by Roberta Piacentini, Laura Centi, Mattia Miotto, Edoardo Milanetti, Lorenzo Di Rienzo, Martina Pitea, Paolo Piazza, Giancarlo Ruocco, Alberto Boffi and Giacomo Parisi
Int. J. Mol. Sci. 2022, 23(10), 5436; https://doi.org/10.3390/ijms23105436 - 13 May 2022
Cited by 16 | Viewed by 2229
Abstract
The present investigation focuses on the analysis of the interactions among human lactoferrin (LF), SARS-CoV-2 receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2) receptor in order to assess possible mutual interactions that could provide a molecular basis of the reported preventative effect [...] Read more.
The present investigation focuses on the analysis of the interactions among human lactoferrin (LF), SARS-CoV-2 receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2) receptor in order to assess possible mutual interactions that could provide a molecular basis of the reported preventative effect of lactoferrin against CoV-2 infection. In particular, kinetic and thermodynamic parameters for the pairwise interactions among the three proteins were measured via two independent techniques, biolayer interferometry and latex nanoparticle-enhanced turbidimetry. The results obtained clearly indicate that LF is able to bind the ACE2 receptor ectodomain with significantly high affinity, whereas no binding to the RBD was observed up to the maximum “physiological” lactoferrin concentration range. Lactoferrin, above 1 µM concentration, thus appears to directly interfere with RBD–ACE2 binding, bringing about a measurable, up to 300-fold increase of the KD value relative to RBD–ACE2 complex formation. Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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Review

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23 pages, 4550 KiB  
Review
Lactoferrin as a Human Genome “Guardian”—An Overall Point of View
by Iwona Bukowska-Ośko, Dorota Sulejczak, Katarzyna Kaczyńska, Patrycja Kleczkowska, Karol Kramkowski, Marta Popiel, Ewa Wietrak and Paweł Kowalczyk
Int. J. Mol. Sci. 2022, 23(9), 5248; https://doi.org/10.3390/ijms23095248 - 8 May 2022
Cited by 22 | Viewed by 4434
Abstract
Structural abnormalities causing DNA modifications of the ethene and propanoadducts can lead to mutations and permanent damage to human genetic material. Such changes may cause premature aging and cell degeneration and death as well as severe impairment of tissue and organ function. This [...] Read more.
Structural abnormalities causing DNA modifications of the ethene and propanoadducts can lead to mutations and permanent damage to human genetic material. Such changes may cause premature aging and cell degeneration and death as well as severe impairment of tissue and organ function. This may lead to the development of various diseases, including cancer. In response to a damage, cells have developed defense mechanisms aimed at preventing disease and repairing damaged genetic material or diverting it into apoptosis. All of the mechanisms described above are part of the repertoire of action of Lactoferrin—an endogenous protein that contains iron in its structure, which gives it numerous antibacterial, antiviral, antifungal and anticancer properties. The aim of the article is to synthetically present the new and innovative role of lactoferrin in the protection of human genetic material against internal and external damage, described by the modulation mechanisms of the cell cycle at all its levels and the mechanisms of its repair. Full article
(This article belongs to the Special Issue Lactoferrin, the Moonlighting Protein of Innate Immunity)
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