PMID: 

Viruses. 2019 01 11 ;11(1). Epub 2019 Jan 11. PMID: 30641890

Abstract Title: 

Bovine Lactoferrin Prevents Influenza A Virus Infection by Interfering with the Fusogenic Function of Viral Hemagglutinin.

Abstract: 

Bovine lactoferrin (bLf) is an iron-binding glycoprotein folded in two symmetric globular lobes (N- and C-lobes) with potent antimicrobial and immunomodulatory activities. Recently, we have shown that bLf, and in particular its C-lobe, interacts with influenza A virus hemagglutinin and prevents infection by different H1 and H3 viral subtypes. Influenza virus hemagglutinin (HA), and in particular its highly conserved fusion peptide involved in the low-pH-mediated fusion process, plays a significant role in the early steps of viral infection and represents an attractive target for the development of anti-influenza drugs. In the present research, we further investigated the influence of low pH on the interactions between bLf and influenza A H1N1 virus by different techniques, such as enzyme-linked immunosorbent assay, electron microscopy, hemolysis inhibition assay, and time course assay. Our results demonstrate that lactoferrin interaction with influenza hemagglutinin at low pH induces alterations that stabilize the conformation of the hemagglutinin, resulting in the inhibition of the fusion peptide activity. Taken together, our data allowed to better characterize the HA-specific inhibiting activity of bLf and to confirm HA as a good target for drug development.

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PMID: 

J Infect Chemother. 2014 Nov ;20(11):666-71. Epub 2014 Aug 30. PMID: 25182867

Abstract Title: 

Lactoferrin for prevention of common viral infections.

Abstract: 

Although lactoferrin has many biological functions, the host-protective effects against pathogenic microorganisms including bacteria, fungi, and viruses are regarded as one of the most important. Here, we review research on the protective role of lactoferrin administration against common viral infections. Many studies have shown the in vitro antiviral activity of lactoferrin against viral pathogens that cause common infections such as the common cold, influenza, gastroenteritis, summer cold, and herpes, where lactoferrin inhibits mainly viral attachment to the target cells. Recently, studies indicating the in vivo protective effects of lactoferrin by oral administration against common viral infections have been increasing. For instance, norovirus is an extremely important emerging human pathogen that causes a majority of gastroenteritis outbreaks worldwide that may be a target candidate for lactoferrin. Lactoferrin consumption reduced the incidence of noroviral gastroenteritis in children and a similar effect was observed in a wide range of ages in a preliminary survey. A recent in vitro study reported that lactoferrin inhibits both cellular attachment of the murine norovirus, a virus closely-related to the human norovirus, and viral replication in the cells by inducing antiviral cytokines interferon (IFN)-α/β. Lactoferrin administration also enhances NK cell activity and Th1 cytokine responses, which lead to protection against viral infections. In conclusion, lactoferrin consumption may protect the host from viral infections through inhibiting the attachment of a virus to the cells, replication ofthe virus in the cells, and enhancement of systemic immune functions.

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PMID: 

Liver Int. 2010 Apr ;30(4):623-32. Epub 2010 Jan 29. PMID: 20136718

Abstract Title: 

Lactoferrin protects against concanavalin A-induced liver injury in mice.

Abstract: 

BACKGROUND: Liver diseases, caused by viral infection, autoimmune conditions, alcohol ingestion or the use of certain drugs, are a significant health issue, as many can develop into liver failure. Lactoferrin (Lac) is an iron-binding glycoprotein that belongs to the transferrin family. Owing to its multiple biological functions, Lac has been evaluated in a number of clinical trials to treat infections, inflammation and cancer.AIM: The present study aims to reveal a profound hepatoprotective effect of Lac, using a mouse model of Concanavalin A (Con A)-induced hepatitis, which mimics the pathophysiology of human viral and autoimmune hepatitis.METHOD: C57Bl/6J mice were injected with bovine Lac following Con A challenge. The effects of Lac on interferon (IFN)-gamma and interleukin (IL)-4 expression were determined. The roles of Lac on T-cell apoptosis and activation, and leukocytes infiltration were examined.RESULT: The data demonstrated that the protective effect of Lac was attributed to its ability to inhibit T-cell activation and production of IFN-gamma, as well as to suppress IL-4 production by hepatic natural killer T cells.CONCLUSION: These findings indicate a great therapeutic potential of Lac in treating in treating inflammatory hepatitis and possibly other inflammatory diseases.

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PMID: 

Oncol Res. 2008 ;17(5):193-203. PMID: 18980016

Abstract Title: 

In vitro antioxidative potential of lactoferrin and black tea polyphenols and protective effects in vivo on carcinogen activation, DNA damage, proliferation, invasion, and angiogenesis during experimental oral carcinogenesis.

Abstract: 

The present study was designed to evaluate the in vitro antioxidant potential of bovine lactoferrin (bLF) and black tea polyphenols [Polyphenon-B (P-B)] as well as in vivo inhibitory effects on the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinomas. Antioxidant activity was screened using a panel of assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), hydroxyl radical anion (OH*), superoxide anion (O2*-), and nitric oxide (NO) radical scavenging assays as well as assay for reducing power. The chemopreventive potential of bLF and P-B was assessed in the HBP model based on the modulatory effects on DMBA-induced oxidative DNA damage as well as the expression of proteins associated with carcinogen activation (CYP1A1, CYP1B1), cell proliferation [cyclin D1, proliferating cell nuclear antigen (PCNA), glutathione S-transferase pi (GST-P)], angiogenesis [vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR1)], and invasion and metastasis [matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of MMP-2 (TIMP-2)]. Both bLF and P-B showed high radical scavenging activity and reductive potential. Although administration of bLF and P-B alone suppressed DMBA-induced HBP tumors, combined administration of bLF and P-B was more effective in inhibiting HBP carcinogenesis by inhibiting oxidative DNA damage, carcinogen activation, cell proliferation, invasion, and angiogenesis. Our study suggests that the antioxidative property of bLF and P-B may be responsible for chemoprevention of HBP carcinogenesis by modulating multiple molecular targets.

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PMID: 

Lab Invest. 2014 Nov ;94(11):1188-99. Epub 2014 Jul 28. PMID: 25068657

Abstract Title: 

Lactoferrin suppresses the Epstein-Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9.

Abstract: 

Epstein-Barr virus (EBV) infection contributes to tumorigenesis of various human malignancies including nasopharyngeal carcinoma (NPC). EBV triggers innate immune and inflammatory responses partly through Toll-like receptor (TLR) signaling. Lactoferrin (LF), with its anti-inflammatory properties, is an important component of the innate immune system. We previously reported that LF protects human B lymphocytes from EBV infection by its ability to bind to the EBV receptor CD21, but whether LF can suppress EBV-induced inflammation is unclear. Here, we report that LF reduced synthesis of IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by EBV in macrophages via its suppression of NF-κB activity. LF interacted with TLR2 and interfered with EBV-triggered TLR2-NF-κB activation. LF inhibited the ability of TLR9 to recognize dsDNA by binding to its co-receptor CD14, which blocked the interaction between CD14 and TLR9. EBV-induced inflammation was thus aggravated in the presence ofCD14. In addition, LF expression levels were significantly downregulated in NPC specimens, and correlated inversely with IL-8 and MCP-1 expression. These findings suggest that LF may suppress the EBV-induced inflammatory response through interfering with the activation of TLR2 and TLR9.

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PMID: 

Cell Biochem Funct. 2017 Jan ;35(1):33-41. Epub 2017 Jan 3. PMID: 28052347

Abstract Title: 

Apoptotic effects of bovine apo-lactoferrin on HeLa tumor cells.

Abstract: 

Lactoferrin (Lf), a cationic iron-binding glycoprotein of 80 kDa present in body secretions, is known as a compound with marked antimicrobial activity. In the present study, the apoptotic effect of iron-free bovine lactoferrin (apo-bLf) on human epithelial cancer (HeLa) cells was examined in association with reactive oxygen species and glutathione (GSH) levels. Apoptotic effect of iron-free bovine lactoferrin inhibited the growth of HeLa cells after 48 hours of treatment while the diferric-bLf was ineffective in the concentration range tested (from 1 to 12.5 μM). Western blot analysis showed that key apoptotic regulators including Bax, Bcl-2, Sirt1,Mcl-1, and PARP-1 were modulated by 1.25 μM of apo-bLf. In the same cell line, apo-bLf induced apoptosis together with poly (ADP-ribose) polymerase cleavage, caspase activation, and a significant drop of NAD. In addition, apo-bLf-treated HeLa cells showed a marked increase of reactive oxygen species level and a significant GSH depletion. On the whole, apo-bLf triggered apoptosis of HeLa cells upon oxygen radicals burst and GSH decrease.

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PMID: 

Eur J Pharm Sci. 2011 Sep 18 ;44(1-2):164-73. Epub 2011 Jul 18. PMID: 21782939

Abstract Title: 

Lactoferrin modified doxorubicin-loaded procationic liposomes for the treatment of gliomas.

Abstract: 

In this study, a brain-targeted chemotherapeutical delivery system, doxorubicin-loaded lactoferrin-modified procationic liposome (DOX-Lf-PCL) was developed, and its therapeutic effect for glioma was evaluated. The uptake profile of various DOX formulations in vitro by primary brain capillary endothelial cells (BCECs) and glioma cell C6 were studied by laser scanning confocal microscope and flow cytometry. An intracranial tumor model of rats was employed to evaluate the therapeutic effect of DOX-Lf-PCLs for glioma. Five groups of glioma-bearing rats (total n=50) were subjected to three cycles of 2.5mg/kg body weight of doxorubicin in different formulations or normal saline (N.S.) and analyzed for survival (median survival time, Kaplan-Meier). The results indicated that compared with the DOX solution or DOX-loaded conventional liposomes (DOX-Lips), DOX-PCLs and DOX-Lf-PCLs showed an improved performance in the uptake efficiency in BCECs and C6 cells. The DOX-Lf-PCLs can inhibit the growth of C6 more efficiently in vitro than other DOX formulations. The endocytosis involved in the DOX-Lf-PCLs uptake of C6 was mediated by both receptor- and absorption-mediated transcytosis. DOX-Lf-PCLs could significantly extend the survival time compared with the N.S. control and other DOX formulations. This study showed that the therapy with DOX-Lf-PCLs offers an effective therapeutic potential for gliomas.

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PMID: 

Biochimie. 2010 Jul ;92(7):880-4. Epub 2010 Mar 25. PMID: 20347004

Abstract Title: 

Lactoferrin induces growth arrest and nuclear accumulation of Smad-2 in HeLa cells.

Abstract: 

Lactoferrin (Lf) is a multifunctional glycoprotein. Due to its anti-inflammatory and anti-cancer properties and the resulting therapeutical potential, lactoferrin is at present focus of a variety of research areas. The regulation of cell growth represents one of the prominent performances of lactoferrin. In this study we found lactoferrin to inhibit proliferation of the human epithelial cancer cell line HeLa. The extent of this growth inhibition was comparable to the one induced by the transforming-growth-factor-beta-1 (TGFbeta1). In contrast to other cell lines where lactoferrin stimulates growth, lactoferrin failed to activate the MAP kinases ERK1/2 or p38 in HeLa cells. However, by immunocytochemistry and cell fractionation experiments, we found that lactoferrin is capable of activating the TGFbeta/Smad-2 pathway. The nuclear accumulation of Smad-2 induced by Lf was comparable in magnitude to the one induced by TGFbeta1. We therefore conclude that the canonical TGFbeta1 pathway is a feasible route for lactoferrin to transduce its antiproliferative effect in HeLa cells, when MAPkinase activation is absent.

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PMID: 

Dig Dis Sci. 2004 Mar ;49(3):425-33. PMID: 15139492

Abstract Title: 

Lactoferrin reduces methotrexate-induced small intestinal damage, possibly through inhibition of GLP-2-mediated epithelial cell proliferation.

Abstract: 

A strategy protecting the small intestine against deleterious side effects associated with anti-cancer therapy is arresting epithelial cell cycling temporally. Since endogenous glucagon-like peptide-2 (GLP-2) is a trophic factor specific for intestinal epithelia, the possibility of inhibiting GLP-2-mediated cell proliferation by lactoferrin, thereby protecting the small intestine against deleterious side effects of anticancer therapy, was investigated. In Caco-2 cells, GLP-2-mediated proliferation was reduced in a dose-dependent manner using lactoferrin. Furthermore, in a rat model for methotrexate-induced mucositis, lactoferrin reduced BrdU incorporation in small intestinal epithelial cells, indicating inhibition of epithelial cell proliferation in vivo. Subsequently, protection against methotrexate-induced intestinal damage was found in corresponding regions. These results show, for the first time, that lactoferrin interferes with GLP-2-induced intestinal epithelial proliferation. It may therefore be hypothesized that lactoferrin protects the intestine against anticancer therapy-induced intestinal damage, via inhibition of GLP-2-induced small intestinal epithelial cell proliferation.

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PMID: 

Mol Pharm. 2010 Dec 6 ;7(6):1995-2005. Epub 2010 Oct 28. PMID: 20957995

Abstract Title: 

Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats.

Abstract: 

The blood-brain barrier (BBB) and multidrug resistance (MDR) are the main causes for poor prognosis of glioma patients after chemotherapy. To explore the way for settling this problem, in this study, a novel antitumor agent loaded drug delivery system, lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine (Lf-PO-Dox/Tet), integrating both BBB and glioma-targeting moiety and MDR inhibitor, was designed and its chemotherapy for glioma rats was evaluated. Biodegradable polymersome (PO) encapsulating both doxorubicin (Dox) and tetrandrine (Tet) was prepared by the thin-film hydration method (PO-Dox/Tet) and then conjugated with lactoferrin (Lf) to yield Lf-PO-Dox/Tet with an average diameter around 220 nm and surface Lf molecule number per polymersome around 40. Compared with PO-DOX, PO-Dox/Tet, and Lf-PO-Dox, Lf-PO-Dox/Tet demonstrated the strongest cytotoxicity against C6 glioma cells and the greatest uptake index by C6 cells. In vivo imaging analysis indicated that Lf-PO labeled with a near-infrared dye could enter the brain and accumulate at the tumor site. Pharmacokinetics and tissue distribution results also showed that Lf-PO-Dox/Tet accumulated more in the right hemisphere than other groups of polymersomes. Pharmacodynamics results revealed that tumor volume of the Lf-PO-Dox/Tet group was significantly smaller than that of other therapeutic groups, and the median survival time of Lf-PO-Dox/Tet group was longer than that of Lf-PO-Dox group and significantly longer than those of the other three therapeutic groups. These results suggested that Lf-PO-Dox/Tet could have therapeutic potential for gliomas.

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