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Kowalczyk, P.; Kaczyńska, K.; Kleczkowska, P.; Bukowska-Ośko, I.; Kramkowski, K.; Sulejczak, D. Lactoferrin's Characteristics and Properties. Encyclopedia. Available online: https://encyclopedia.pub/entry/49663 (accessed on 23 July 2024).
Kowalczyk P, Kaczyńska K, Kleczkowska P, Bukowska-Ośko I, Kramkowski K, Sulejczak D. Lactoferrin's Characteristics and Properties. Encyclopedia. Available at: https://encyclopedia.pub/entry/49663. Accessed July 23, 2024.
Kowalczyk, Paweł, Katarzyna Kaczyńska, Patrycja Kleczkowska, Iwona Bukowska-Ośko, Karol Kramkowski, Dorota Sulejczak. "Lactoferrin's Characteristics and Properties" Encyclopedia, https://encyclopedia.pub/entry/49663 (accessed July 23, 2024).
Kowalczyk, P., Kaczyńska, K., Kleczkowska, P., Bukowska-Ośko, I., Kramkowski, K., & Sulejczak, D. (2023, September 26). Lactoferrin's Characteristics and Properties. In Encyclopedia. https://encyclopedia.pub/entry/49663
Kowalczyk, Paweł, et al. "Lactoferrin's Characteristics and Properties." Encyclopedia. Web. 26 September, 2023.
Lactoferrin's Characteristics and Properties
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27092941

Lactoferrin (LF) is a component of the whey protein of milk of most mammals, probably with the exception of dogs and rats. The concentration of lactoferrin in milk depends on the phase of lactation. It has been proven that colostrum can contain up to seven times more LF than mature milk. Human body cells can produce lactoferrin and it is also found in many organs and cells of the human body. Its presence has been confirmed in kidneys, lungs, gallbladder, pancreas, intestine, liver, prostate, saliva, tears, sperm, cerebrospinal fluid, urine, bronchial secretions, vaginal discharge, synovial fluid, umbilical cord blood, blood plasma, and cells of the immune system. It is present wherever the body needs quick and effective protection against external threats.

lactoferrin oxidative stress immunomodulation

1. Immune System—Effects of Lactoferrin on Foetus, Infants and Reproduction

When discussing lactoferrin, it is often said that it is “unable” to affect the body due to digestion; however, scientific evidence suggests that it is hydrolyzed to stable, immunologically active peptides upon contact with the acidic environment of the gastric juice. Lactoferrin preparations are effective after oral administration, which has been confirmed in numerous studies, including clinical ones [1][2][3][4][5][6]. LF can reach the intestine, mainly in the form of peptide fragments, where they act locally on the microbiota and the immune system associated with the local mucosa, thereby enhancing the immunity of all mucous membranes in the body [7][8][9].
In children suffering from diarrhea, oral lactoferrin both alleviated the course and reduced the frequency [9][10]. Published studies using lactoferrin in children have positively evaluated its use for both gastrointestinal infections and sepsis in neonates, and lactoferrin supply in preterm infants is recommended to be introduced as soon as possible [11][12]. It is also very interesting that, in pregnant women, intravaginal lactoferrin is one of the preventive measures reducing the risk of premature delivery [10][13]. LF supports normal tissue development in the fetus, including normal ossification, adequate iron availability and absorption, protects against infection and inflammation, and benefits both mother and fetus [14]. LF acts as a probiotic, protecting the lower genital tract and preventing the consequences of inflammation both during pregnancy and before pregnancy, thus aiding fertility. Lactoferrin is present in the follicular fluid, but results of studies on its effect on oocyte maturation and quality are inconclusive [15][16]. The role of lactoferrin in male fertility is still under intense debate and research [17][18]. It can protect against infections of the male genital tract and regulate iron levels in sperm, thus influencing its quality. This appears to be a good potential marker of sperm quality [17]. This issue is the subject of ongoing clinical trials—ClinicalTrials.gov Identifier: NCT05171504.

2. Antitoxic and Antipathogenic Properties

Numerous studies have confirmed the beneficial effects of LF on the intestinal epithelium. This protein stimulates the growth, differentiation and secretory activity of epithelial cells, which optimizes the digestive processes and absorption of nutrients and protects against the action of pathogens and food allergens [19][20]. LF also protects the intestinal epithelium from the toxic effects of reactive oxygen species (ROS), bacterial toxins and xenobiotics such as nonsteroidal anti-inflammatory drugs (NSAIDs) [21][22][23][24]. Importantly, LF also protects against gastrointestinal tract infections, both viral and bacterial, fungal and protozoal [1][25]. Many tests have demonstrated the protective effect of LF in the states of endotoxemia, bacteremia, sepsis and necrotic enteritis in neonates [3][4][26][27][28][29], in inflammatory colitis [30][31] and after partial bowel resection [32]. LF has antibacterial properties in relation to Gram-negative and Gram-positive bacteria, thanks to which it is helpful for fighting pathogens, prevents the formation of biofilm by pathogenic bacteria, such as Staphylococcus aureus or blue oil rod (Pseudomonas aeruginosa) [25][33]. LF supports the treatment of gastric infection caused by Helicobacter pylori [34]. The mechanism of action of LF may, inter alia, include the direct inhibition or killing of microbial cells, activation/inhibition of the immune system, or enhancement of intestinal epithelial tightness by stimulating the production of tight junction proteins. In addition, the binding of iron by LF makes its absence associated with a concomitant halt in bacterial growth, which protects the body from infection. [35]. It also has an immunomodulating effect, stimulating the body to synthesize cytokines and chemokines as well as accelerating the maturation of cells of the immune system [36][37][38][39].
Human lactoferrin (abbreviated as hLF,) possesses 77% similarities with the bovine form (bLF) in the aspect of amino acid sequences, although bovine lactoferrin is usually studied, because it is easier to obtain. It has been estimated that in a glass of cow’s milk we will find about 25-75 mg of this protein. At the same time, it seems that bLF is not an ideal choice due to differences that may alter its antiviral and antimicrobial potential when used in human therapy, but some authors highlight its stronger antimicrobial activity [40].

3. Anticancer Activity

One of the many properties of LF is its anticancer activity. This may be related not only to preventing antioxidant stress and inflammation, which contribute to DNA damage and tumorigenesis, but also to preventing the development of, or inhibiting, cancer by stimulating the adaptive immune response [41]. This is the case for colorectal cancer, the epidemiology of which is mainly related to age and lifestyle factors [42] and in the case of childhood leukemia where long-term consumption of breast milk may prevent the risk of developing leukemia due to the immunoprotective properties of the LF present [43]. Furthermore, LF may directly inhibit proliferation, survival, migration, metastasis and accelerating cancer cell death [44][45].
It has been confirmed that, in the presence of LF, various cancer cells undergo remarkable damage such as cell cycle arrest, damage to the cytoskeleton and induction of apoptosis, as well as decreased cell migration [44][46]. The postulated property of LF by which it activates signaling pathways to generate deleterious effects on cancer cells may be interaction with proteoglycans, glycosaminoglycans, and sialic acid, high levels of which are presented by cancer cells. This may also explain the high cytotoxic selectivity of LF against cancer cells only [45][46][47]. Besides, the ability of LF to enter the cell nucleus is likely the primary mechanism by which it exerts its pleiotropic functions, including anticancer. Nuclear LF (called delta) acts as a transcription factor and causes activation of expression target genes such as Bax, SelH, DcpS, UBE2E1, Skp1 and GTF2F2 and shows the anticancer, anti-proliferating and pro-apoptotic activities [48][49][50][51]. This corresponds to decreased levels of LF and delta LF expression in tumor cells, which often correlates with greater tumor progression and poor prognosis [50][52][53].
LF also binds iron, which is heavily involved in the metabolic requirements of some cancer cells, and blocks angiogenesis, i.e., prevents the formation of new blood vessels, thereby inhibiting tumor growth and metastasis or directing the tumor toward apoptosis [54][55].
An interesting feature of LF that deserves attention, in addition to its proven safety and its low antigenicity and selectivity for cancer cells, which could be used in brain tumor therapy, is its passage through the blood–brain barrier [45].

4. Aging and Aging-Related Diseases

Aging can be defined as: “the progressive accumulation of changes with time associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age”, and the factors that lead to aging: “the sum of the deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it” [56] and “changes in molecular structure and, hence, function” [57]. In summary, aging is a complex natural phenomenon occurring as a consequence of the passage of time, environmental factors and genetics that increase susceptibility to developing systemic diseases, including metabolic disorders (diabetes mellitus), cardiovascular, neurodegenerative and respiratory diseases as well as rheumatoid arthritis, cancers or dementia [58][59][60][61].
The pleiotropic anti-aging effect of LF is related to its antioxidant, anti-inflammatory and anticancer effects, as well as the assurance of neuroprotection or the alleviation of mitochondrial dysfunction and systemic disorders [58].
LF antioxidant potential leads to cells’ and organs’ protection finally extending its lifespan [62]. In addition, due to regulation of numerous genes expression (inhibition of NF-κB, mTORC1 and caspase via the Erk and Akt pathways), LF regulates cell growth, proliferation, apoptosis and inflammation. It suppresses the senescence and apoptosis of mesenchymal stem cells (MSCs) [63][64], promotes both the formation of granulation tissue and re-epithelialization (proliferation and migration of fibroblasts and keratinocytes stimulation and enhancement of extracellular matrix components synthesis) [65][66]. Moreover, due to the induction of the targeted apoptosis of senescent cells or the disruption of the senescence-associated secretory phenotype (SASP), LF restores tissue homeostasis [60][61]. Interestingly, LF usefulness has been shown for treatment, diagnosis or monitoring age-related diseases [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. For example, it may act as a neuroprotective agent in Alzheimer’s disease (AD) and Parkinson’s disease (PD) [72][76][77] leading to the improvement of cognitive function and attenuation of brain senescence [82]. The possible mechanism of LF action includes iron-binding dependent manner (upregulation of divalent metal transporter 1 (DMT1) and transferrin receptor (TFR) and downregulation ferroportin 1 (Fpn1)) [78][79] and/or iron-binding independent manner (regulation of the p-Akt/PTEN or the ERK-CREB pathway in HIF-1-dependent manner) [79][80][81]. Furthermore, LF preserves mitochondrial calcium homeostasis in degenerated dopaminergic neurons [83]. Moreover, LF regulates body fat metabolism limiting obesity (probable downregulation of adipogenic genes and upregulation of fatty acid synthase and acetyl CoA carboxylase in adipocytes) [84][85] and glucose metabolism in patients with type 2 diabetes mellitus via improvement of the insulin-signaling response in adipocytes (up-phosphorylation of Akt serine 473 and up-expression of glucose transport 4 and insulin receptor 1) [68][85][86][87].

5. Lactoferrin in the Human Diet and Therapy of Diseases

Lactoferrin is an important component in the human diet. Due to its high nutritional value, its antibacterial, antiviral, anti-cancer properties and regulation of the activity of the immune system [36], it has also been used in the pharmaceutical and food industries and in the production of feed additives. Currently, we can find it in products such as dietary supplements and infant formula. Lactoferrin obtained from cow’s milk is used, among others, in the production of infant formulas, foodstuffs for special medical purposes, milk, yoghurt drinks, ice cream and cookies, dietary supplements, and processed cereal products. It is also appreciated in the cosmetic (e.g., in cosmetics and toothpaste) and pharmaceutical industries [11][14][88][89].
It is also worth mentioning that LF, as a naturally occurring protein in saliva and produced by salivary glands in the oral cavity, has protective properties and is supposed to provide homeostasis in the oral cavity [36]. The ability to bind iron ions by LF provides antibacterial activity in the oral cavity. The use of products with LF further supplements it in the oral or nasal cavity, thus strengthening the first protective barrier against bacteria and viruses from the outside [90][91][92][93][94][95]. The effectiveness of LF has been established in numerous in vitro, animal, and human studies in which LF, used in oral and vaginal formulations, positively altered the ecosystem of the reproductive tract by eliminating pathogenic microorganisms and increasing Lactobacillus species, re-establishing the state of eubiosis and protecting from dangerous consequences of dysbiosis, such as premature labor or miscarriage [96][97].
So far, most of the data on the positive effects of LF in pathological conditions are mainly based on studies in animal models. To date, studies in animal models have shown a significant increase in survival in rodents when sepsis developed after injection of E. coli [98]. Subsequent work revealed the strong anti-inflammatory effect of LF in models with induced gastritis or enteritis. However, the most promising results come from experiments based on the administration of lactoferrin to subjects with immature digestive systems (possibly due to an underdeveloped intestinal microbiome). Calves and newborn rats were characterized by better absorption of nutrients and a significant increase in intestinal villi length and stimulation of the development of the immune system [9][94][99][100][101][102]. Lactoferrin was reported to protect against oxidative stress-induced mitochondrial dysfunction and DNA damage, thus modulating innate immune responsiveness which can further alter the production of immune regulatory mediators that are important for directing the development of adaptive immune function [8][21][39][103][104][105]. Such LF action was revealed both in cell culture and within an animal model of endotoxemia. In fact, mitochondria from lipopolysaccharide (LPS)-treated animals released significantly higher amounts of H2O2 than those isolated from LF-pre-treated plus LPS-challenged animals [105]. This mechanism is of fundamental protective importance at the beginning of an infection. After the infection phase, lactoferrin shows a strong immunotropic effect: it stimulates the cells of the immune system to mature rapidly and enhance the immune response.
In order to not rely only on animal studies, it is worth recalling clinical trials. Among adults, it was possible to notice an improvement in the condition of people suffering from chronic H. pylori infection (the most common cause of peptic ulcer disease) in a form resistant to conventional treatment [106]. The results of studies involving patients suffering from various types of cancer are also promising, although preliminary. The anticancer effects of supplementation with LF in the gastrointestinal tract cancer and protection against colon cancer, stomach cancer, liver cancer and pancreatic cancer may be explained by the antioxidant properties of lactoferrin [103][107][108][109][110] (Figure 1).
Figure 1. Protective role of lactoferrin in eukaryotic cell.
Nevertheless, if we consider using LF in therapy, the form of its administration is very important. Lactoferrin is a hydrophilic substance, therefore in the non-liposomal version it has very limited absorption from the stomach [104]. In free form, it is decomposed there by hydrochloric acid and enzymes (proteases). Therefore, the bioavailability of the free form of lactoferrin may be limited. The use of small liposome vesicles may be beneficial in this case [111][112][113]. Nanoliposomes protect lactoferrin from destruction by digestive juices, allowing the intact protein to pass into the duodenum, from there into the general circulation, ensuring its high bioavailability [114] and impact on iron ions homeostasis, the skeletal system and, of course, the immune system.
LF administered in a phosphatidylcholine encapsulated form also has the potential to penetrate deep into the mucosa, and due to the small size of the nanoliposome (100 nm) compared to the virus size (150 nm), it is more competitive in reaching receptors on target cells where it settles in front of the virus [111][112]. It is important to note that the mucous membranes lining the oral or nasal cavities are very permeable, so this additional protection against viruses based on nanolactoferrin is very relevant.

References

  1. Artym, J.; Zimecki, M. Milk-derived proteins and peptides in clinical trials. Postepy Hig. Med. Dosw. 2013, 67, 800–816.
  2. Chen, K.; Chai, L.; Li, H.; Zhang, Y.; Xie, H.-M.; Shang, J.; Tian, W.; Yang, P.; Jiang, A.C. Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial. Nutrition 2016, 32, 222–227.
  3. Manzoni, P.; Rinaldi, M.; Cattani, S.; Pugni, L.; Romeo, M.G.; Messner, H.; Stolfi, I.; Decembrino, L.; Laforgia, N.; Vagnarelli, F.; et al. Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomized Trial. JAMA 2009, 302, 1421–1428.
  4. Sherman, M.P.; Sherman, J.; Arcinue, R.; Niklas, V. Randomized Control Trial of Human Recombinant Lactoferrin: A Substudy Reveals Effects on the Fecal Microbiome of Very Low Birth Weight Infants. J. Pediatr. 2016, 173, S37–S42.
  5. Johnston, W.H.; Ashley, C.; Yeiser, M.; Harris, C.L.; Stolz, S.I.; Wampler, J.L.; Wittke, A.; Cooper, T.R. Growth and tolerance of formula with lactoferrin in infants through one year of age: Double-blind, randomized, controlled trial. BMC Pediatr. 2015, 15, 173.
  6. Manzoni, P. Clinical Studies of Lactoferrin in Neonates and Infants: An Update. Breastfeed. Med. 2019, 14, S25–S27.
  7. Baker, H.M.; Baker, E.N. A structural perspective on lactoferrin function. Biochem. Cell Biol. 2012, 90, 320–328.
  8. Debbabi, H.; Dubarry, M.; Rautureau, M.; Tomé, D. Bovine lactoferrin induces both mucosal and systemic immune response in mice. J. Dairy Res. 1998, 65, 283–293.
  9. Baldi, A.; Ioannis, P.; Chiara, P.; Eleonora, F.; Roubini, C.; Vittorio, D. Biological effects of milk proteins and their peptides with emphasis on those related to the gastrointestinal ecosystem. J. Dairy Res. 2005, 72, 66–72.
  10. Balmer, S.E.; Scott, P.H.; Wharton, B.A. Diet and faecal flora in the newborn: Lactoferrin. Arch. Dis. Child. 1989, 64, 1685–1690.
  11. Cleminson, J.S.; Zalewski, S.P.; Embleton, N.D. Nutrition in the preterm infant: What’s new? Curr. Opin. Clin. Nutr. Metab. Care 2016, 19, 220–225.
  12. ELFIN Investigators Group. Enteral lactoferrin supplementation for very preterm infants: A randomised placebo-controlled trial. Lancet 2019, 393, 423–433.
  13. Bukowska-Osko, I.; Popiel, M.; Kowalczyk, P. The Immunological Role of the Placenta in SARS-CoV-2 Infection-Viral Transmission, Immune Regulation, and Lactoferrin Activity. Int. J. Mol. Sci. 2021, 22, 5799.
  14. Artym, J.; Zimecki, M.; Kruzel, M. Lactoferrin for Prevention and Treatment of Anemia and Inflammation in Pregnant Women: A Comprehensive Review. Biomedicines 2021, 9, 898.
  15. Yanaihara, A.; Mitsukawa, K.; Iwasaki, S.; Otsuki, K.; Kawamura, T.; Okai, T. High concentrations of lactoferrin in the follicular fluid correlate with embryo quality during in vitro fertilization cycles. Fertil. Steril. 2007, 87, 279–282.
  16. Mostafa, M.H.; Faisal, M.M.; Mohamed, N.R.; Idle, F.H. Effect of Follicular Fluid Lactoferrin Level on Oocytes Quality and Pregnancy Rate in Intracytoplasmic Sperm Injection Cycles. Open J. Obstet. Gynecol. 2019, 9, 745–754.
  17. Omes, C.; De Amici, M.; Tomasoni, V.; Todaro, F.; Torre, C.; Nappi, R.E. Myeloperoxidase and lactoferrin expression in semen fluid: Novel markers of male infertility risk? Immunobiology 2020, 225, 151999.
  18. Buckett, W.M.; Luckas, M.J.; Gazvani, M.; Aird, I.A.; Lewis-Jones, D.I. Seminal plasma lactoferrin concentrations in normal and abnormal semen samples. J. Androl. 1997, 18, 302–304.
  19. Zhang, P.; Sawicki, V.; Lewis, A.; Hanson, L.; Nuijens, J.H.; Neville, M.C. Human Lactoferrin in the Milk of Transgenic Mice Increases Intestinal Growth in Ten-Day-Old Suckling Neonates. Adv. Exp. Med. Biol. 2001, 501, 107–113.
  20. Buccigrossi, V.; De Marco, G.; Bruzzese, E.; Ombrato, L.; Bracale, I.; Polito, G.; Guarino, A. Lactoferrin Induces Concentration-Dependent Functional Modulation of Intestinal Proliferation and Differentiation. Pediatr. Res. 2007, 61, 410–414.
  21. Shoji, H.; Oguchi, S.; Shinohara, K.; Shimizu, T.; Yamashiro, Y. Effects of Iron-Unsaturated Human Lactoferrin on Hydrogen Peroxide-Induced Oxidative Damage in Intestinal Epithelial Cells. Pediatr. Res. 2007, 61, 89–92.
  22. Hirotani, Y.; Ikeda, K.; Kato, R.; Myotoku, M.; Umeda, T.; Ijiri, Y.; Tanaka, K. Protective Effects of Lactoferrin against Intestinal Mucosal Damage Induced by Lipopolysaccharide in Human Intestinal Caco-2 Cells. Yakugaku Zasshi 2008, 128, 1363–1368.
  23. Kruzel, M.L.; Harari, Y.; Chen, C.-Y.; Castro, G.A. Lactoferrin Protects Gut Mucosal Integrity During Endotoxemia Induced by Lipopolysaccharide in Mice. Inflammation 2000, 24, 33–44.
  24. Troost, F.J.; Saris, W.H.M.; Brummer, R.-J.M. Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers. Eur. J. Clin. Nutr. 2003, 57, 1579–1585.
  25. Jenssen, H.; Hancock, R.E.W. Antimicrobial properties of lactoferrin. Biochimie 2009, 91, 19–29.
  26. Meyer, M.P.; Alexander, T. Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. J. Neonatal Perinat. Med. 2017, 10, 249–255.
  27. Chissov, V.I.; Iakubovskaia, R.I.; Nemtsova, E.R.; Osipova, N.; Edeleva, N.V.; Utkin, M.M.; Zviagin, A.A. Antioxidants treatment of severe post-operative pyoinflammatory and septic complications. Khirurgiia 2008, 11, 14–19.
  28. Edde, L.; Hipolito, R.B.; Hwang, F.F.Y.; Headon, D.R.; Shalwitz, R.A.; Sherman, M.P. Lactoferrin protects neonatal rats from gut-related systemic infection. Am. J. Physiol. Liver Physiol. 2001, 281, G1140–G1150.
  29. Kruzel, M.L.; Zimecki, M.; Actor, J.K. Lactoferrin in a Context of Inflammation-Induced Pathology. Front. Immunol. 2017, 8, 1438.
  30. Alexander, D.B.; Iigo, M.; Abdelgied, M.; Ozeki, K.; Tanida, S.; Joh, T.; Takahashi, S.; Tsuda, H. Bovine lactoferrin and Crohn’s disease: A case study. Biochem. Cell Biol. 2017, 95, 133–141.
  31. Li, L.; Ren, F.; Yun, Z.; An, Y.; Wang, C.; Yan, X. Determination of the effects of lactoferrin in a preclinical mouse model of experimental colitis. Mol. Med. Rep. 2013, 8, 1125–1129.
  32. Wu, J.; Chen, J.; Wu, W.; Shi, J.; Zhong, Y.; van Tol, E.A.F.; Tang, Q.; Cai, W. Enteral supplementation of bovine lactoferrin improves gut barrier function in rats after massive bowel resection. Br. J. Nutr. 2014, 112, 486–492.
  33. Lizzi, A.R.; Carnicelli, V.; Clarkson, M.M.; DI Giulio, A.; Oratore, A. Lactoferrin Derived Peptides: Mechanisms of Action and their Perspectives as Antimicrobial and Antitumoral Agents. Mini Rev. Med. Chem. 2009, 9, 687–695.
  34. Tolone, S.; Pellino, V.; Vitaliti, G.; Lanzafame, A.; Tolone, C. Evaluation of Helicobacter Pylori eradication in pediatric patients by triple therapy plus lactoferrin and probiotics compared to triple therapy alone. Ital. J. Pediatr. 2012, 38, 63.
  35. Arnold, R.R.; Brewer, M.; Gauthier, J.J. Bactericidal activity of human lactoferrin: Sensitivity of a variety of microorganisms. Infect. Immun. 1980, 28, 893–898.
  36. Siqueiros-Cendón, T.; Arévalo-Gallegos, S.; Iglesias-Figueroa, B.F.; García-Montoya, I.A.; Salazar-Martínez, J.; Rascón-Cruz, Q. Immunomodulatory effects of lactoferrin. Acta Pharmacol. Sin. 2014, 35, 557–566.
  37. Drago-Serrano, M.E.; Campos-Rodríguez, R.; Carrero, J.C.; De La Garza, M. Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Int. J. Mol. Sci. 2017, 18, 501.
  38. Actor, J.K.; Hwang, S.-A.; Kruzel, M.L. Lactoferrin as a Natural Immune Modulator. Curr. Pharm. Des. 2009, 15, 1956–1973.
  39. Artym, J.; Kocięba, M.; Zaczyńska, E.; Adamik, B.; Kübler, A.; Zimecki, M.; Kruzel, M. Immunomodulatory properties of human recombinant lactoferrin in mice: Implications for therapeutic use in humans. Adv. Clin. Exp. Med. 2018, 27, 391–399.
  40. Tomita, M.; Wakabayashi, H.; Yamauchi, K.; Teraguchi, S.; Hayasawa, H. Bovine lactoferrin and lactoferricin derived from milk: Production and applications. Biochem. Cell Biol. 2002, 80, 109–112.
  41. Bielecka, M.; Cichosz, G.; Czeczot, H. Antioxidant, antimicrobial and anticarcinogenic activities of bovine milk proteins and their hydrolysates—A review. Int. Dairy J. 2021, 127, 105208.
  42. Ramírez-Rico, G.; Drago-Serrano, M.E.; León-Sicairos, N.; de la Garza, M. Lactoferrin: A Nutraceutical with Activity against Colorectal Cancer. Front. Pharmacol. 2022, 13, 855852.
  43. Amitay, E.L.; Keinan-Boker, L. Breastfeeding and Childhood Leukemia Incidence. JAMA Pediatrics 2015, 169, e151025.
  44. Zhang, Y.; Lima, C.F.; Rodrigues, L.R. Anticancer effects of lactoferrin: Underlying mechanisms and future trends in cancer therapy. Nutr. Rev. 2014, 72, 763–773.
  45. Cutone, A.; Rosa, L.; Ianiro, G.; Lepanto, M.S.; Bonaccorsi di Patti, M.C.; Valenti, P.; Musci, G. Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action. Biomolecules 2020, 10, 456.
  46. Rascón-Cruz, Q.; Espinoza-Sánchez, E.A.; Siqueiros-Cendón, T.S.; Nakamura-Bencomo, S.I.; Arévalo-Gallegos, S.; Iglesias-Figueroa, B.F. Lactoferrin: A Glycoprotein Involved in Immunomodulation, Anticancer, and Antimicrobial Processes. Molecules 2021, 26, 205.
  47. Iglesias-Figueroa, B.F.; Siqueiros-Cendón, T.S.; Gutierrez, D.A.; Aguilera, R.J.; Espinoza-Sánchez, E.A.; Arévalo-Gallegos, S.; Varela-Ramirez, A.; Rascón-Cruz, Q. Recombinant human lactoferrin induces apoptosis, disruption of F-actin structure and cell cycle arrest with selective cytotoxicity on human triple negative breast cancer cells. Apoptosis 2019, 24, 562–577.
  48. Mariller, C.; Benaïssa, M.; Hardivillé, S.; Breton, M.; Pradelle, G.; Mazurier, J.; Pierce, A. Human delta-lactoferrin is a transcription factor that enhances Skp1 (S-phase kinase-associated protein) gene expression. FEBS J. 2007, 274, 2038–2053.
  49. Hardivillé, S.; Escobar-Ramírez, A.; Pina-Canceco, S.; Elass, E.; Pierce, A. Delta-lactoferrin induces cell death via the mitochondrial death signaling pathway by upregulating bax expression. BioMetals 2014, 27, 875–889.
  50. Mariller, C.; Hardivillé, S.; Hoedt, E.; Benaïssa, M.; Mazurier, J.; Pierce, A. Proteomic approach to the identification of novel delta-lactoferrin target genes: Characterization of DcpS, an mRNA scavenger decapping enzyme. Biochimie 2009, 91, 109–122.
  51. Hoedt, E.; Chaoui, K.; Huvent, I.; Mariller, C.; Monsarrat, B.; Burlet-Schiltz, O.; Pierce, A. SILAC-Based Proteomic Profiling of the Human MDA-MB-231 Metastatic Breast Cancer Cell Line in Response to the Two Antitumoral Lactoferrin Isoforms: The Secreted Lactoferrin and the Intracellular Delta-Lactoferrin. PLoS ONE 2014, 9, e104563.
  52. Siebert, P.D.; Huang, B.C.B. Identification of an alternative form of human lactoferrin mRNA that is expressed differentially in normal tissues and tumor-derived cell lines. Proc. Natl. Acad. Sci. USA 1997, 94, 2198–2203.
  53. Hoedt, E.; Hardivillé, S.; Mariller, C.; Elass, E.; Perraudin, J.-P.; Pierce, A. Discrimination and evaluation of lactoferrin and delta-lactoferrin gene expression levels in cancer cells and under inflammatory stimuli using TaqMan real-time PCR. BioMetals 2010, 23, 441–452.
  54. Rosa, L.; Cutone, A.; Lepanto, M.S.; Paesano, R.; Valenti, P. Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis. Int. J. Mol. Sci. 2017, 18, 1985.
  55. Kazan, H.H.; Urfali-Mamatoglu, C.; Gunduz, U. Iron metabolism and drug resistance in cancer. BioMetals 2017, 30, 629–641.
  56. Harman, D. The aging process. Proc. Natl. Acad. Sci. USA 1981, 78, 7124–7128.
  57. Hayflick, L. Entropy Explains Aging, Genetic Determinism Explains Longevity, and Undefined Terminology Explains Misunderstanding Both. PLoS Genet. 2007, 3, e220.
  58. Li, B.; Zhang, B.; Liu, X.; Zheng, Y.; Han, K.; Liu, H.; Wu, C.; Li, J.; Fan, S.; Peng, W.; et al. The effect of lactoferrin in aging: Role and potential. Food Funct. 2021, 13, 501–513.
  59. Cardoso, A.L.; Fernandes, A.; Aguilar-Pimentel, J.A.; De Angelis, M.H.; Guedes, J.R.; Brito, M.A.; Ortolano, S.; Pani, G.; Athanasopoulou, S.; Gonos, E.S.; et al. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res. Rev. 2018, 47, 214–277.
  60. Birch, J.; Gil, J. Senescence and the SASP: Many therapeutic avenues. Genes Dev. 2020, 34, 1565–1576.
  61. Childs, B.G.; Durik, M.; Baker, D.J.; Van Deursen, J.M. Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat. Med. 2015, 21, 1424–1435.
  62. Martorell, P.; Llopis, S.; Gonzalez, N.; Ramón, D.; Serrano, G.; Torrens, A.; Serrano, J.M.; Navarro, M.; Genovés, S. A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloidβpeptide toxicity inCaenorhabditis elegans. Food Sci. Nutr. 2016, 5, 255–265.
  63. Park, S.Y.; Jeong, A.-J.; Kim, G.-Y.; Jo, A.; Lee, J.E.; Leem, S.-H.; Yoon, J.-H.; Ye, S.K.; Chung, J.W. Lactoferrin Protects Human Mesenchymal Stem Cells from Oxidative Stress-Induced Senescence and Apoptosis. J. Microbiol. Biotechnol. 2017, 27, 1877–1884.
  64. Raghavan, S.; Malayaperumal, S.; Mohan, V.; Balasubramanyam, M. A comparative study on the cellular stressors in mesenchymal stem cells (MSCs) and pancreatic β-cells under hyperglycemic milieu. Mol. Cell. Biochem. 2020, 476, 457–469.
  65. Takayama, Y.; Aoki, R. Roles of lactoferrin on skin wound healing1This article is part of Special Issue entitled Lactoferrin and has undergone the Journal’s usual peer review process. Biochem. Cell Biol. 2012, 90, 497–503.
  66. Tang, L.; Wu, J.; Ma, Q.; Cui, T.; Andreopoulos, F.; Gil, J.; Valdes, J.; Davis, S.; Li, J. Human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization. Br. J. Dermatol. 2010, 163, 38–47.
  67. Moreno-Navarrete, J.M.; Ortega, F.J.; Bassols, J.; Castro, A.; Ricart, W.; Fernández-Real, J.M. Association of Circulating Lactoferrin Concentration and 2 Nonsynonymous LTF Gene Polymorphisms with Dyslipidemia in Men Depends on Glucose-Tolerance Status. Clin. Chem. 2008, 54, 301–309.
  68. Moreno-Navarrete, J.M.; Ortega, F.J.; Bassols, J.; Ricart, W.; Fernández-Real, J.M. Decreased Circulating Lactoferrin in Insulin Resistance and Altered Glucose Tolerance as a Possible Marker of Neutrophil Dysfunction in Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2009, 94, 4036–4044.
  69. Vengen, I.T.; Dale, A.C.; Wiseth, R.; Midthjell, K.; Videm, V. Lactoferrin is a novel predictor of fatal ischemic heart disease in diabetes mellitus type 2: Long-term follow-up of the HUNT 1 study. Atherosclerosis 2010, 212, 614–620.
  70. Fernández-Real, J.M.; García-Fuentes, E.; Moreno-Navarrete, J.M.; Murri-Pierri, M.; Garrido-Sánchez, L.; Ricart, W.; Tinahones, F. Fat Overload Induces Changes in Circulating Lactoferrin That Are Associated With Postprandial Lipemia and Oxidative Stress in Severely Obese Subjects. Obesity 2010, 18, 482–488.
  71. Santos-Silva, A.; Rebelo, I.; Castro, E.; Belo, L.; Catarino, C.; Monteiro, I.; Almeida, M.D.; Quintanilha, A. Erythrocyte damage and leukocyte activation in ischemic stroke. Clin. Chim. Acta 2002, 320, 29–35.
  72. Carro, E.; Bartolome, F.; Bermejo-Pareja, F.; Villarejo-Galende, A.; Molina, J.A.; Ortiz, P.; Calero, M.; Rabano, A.; Cantero, J.L.; Orive, G. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2017, 8, 131–138.
  73. Yu, S.Y.; Sun, L.; Liu, Z.; Huang, X.Y.; Zuo, L.J.; Cao, C.J.; Zhang, W.; Wang, X.M. Sleep disorders in Parkinson’s disease: Clinical features, iron metabolism and related mechanism. PLoS ONE 2013, 8, e82924.
  74. Langhorst, J.; Boone, J. Fecal lactoferrin as a noninvasive biomarker in inflammatory bowel diseases. Drugs Today 2012, 48, 149–161.
  75. Stanczyk, J.; Kowalski, M.L.; Grzegorczyk, J.; Szkudlinska, B.; Jarzebska, M.; Marciniak, M.; Synder, M. RANTES and Chemotactic Activity in Synovial Fluids From Patients With Rheumatoid Arthritis and Osteoarthritis. Mediat. Inflamm. 2005, 2005, 343–348.
  76. González-Sánchez, M.; Bartolome, F.; Antequera, D.; Puertas-Martín, V.; González, P.; Gómez-Grande, A.; Llamas-Velasco, S.; Martín, A.H.-S.; Pérez-Martínez, D.; Villarejo-Galend, A.; et al. Decreased salivary lactoferrin levels are specific to Alzheimer’s disease. EBioMedicine 2020, 57, 102834.
  77. Abdelhamid, M.; Jung, C.-G.; Zhou, C.; Abdullah, M.; Nakano, M.; Wakabayashi, H.; Abe, F.; Michikawa, M. Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-β Generation in J20 Mice. J. Alzheimer’s Dis. 2020, 74, 245–259.
  78. Liu, H.; Wu, H.; Zhu, N.; Xu, Z.; Wang, Y.; Qu, Y.; Wang, J. Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease in mice. J. Neurochem. 2019, 152, 397–415.
  79. Xu, S.-F.; Zhang, Y.-H.; Wang, S.; Pang, Z.-Q.; Fan, Y.-G.; Li, J.-Y.; Wang, Z.-Y.; Guo, C. Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice. Redox Biol. 2018, 21, 101090.
  80. Mohamed, W.A.; Salama, R.M.; Schaalan, M.F. A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: Impact of the p-Akt/PTEN pathway. Biomed. Pharmacother. 2019, 111, 714–723.
  81. Li, Y.-Q.; Guo, C. A Review on Lactoferrin and Central Nervous System Diseases. Cells 2021, 10, 1810.
  82. Zheng, J.; Xie, Y.; Li, F.; Zhou, Y.; Qi, L.; Liu, L.; Chen, Z. Lactoferrin improves cognitive function and attenuates brain senescence in aged mice. J. Funct. Foods 2019, 65, 103736.
  83. Rousseau, E.; Michel, P.P.; Hirsch, E. The Iron-Binding Protein Lactoferrin Protects Vulnerable Dopamine Neurons from Degeneration by Preserving Mitochondrial Calcium Homeostasis. Mol. Pharmacol. 2013, 84, 888–898.
  84. Moreno-Navarrete, J.M.; Ortega, F.J.; Sabater-Masdeu, M.; Ricart, W.; Fernández-Real, J.M. Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes. J. Nutr. Biochem. 2011, 22, 1143–1149.
  85. Moreno-Navarrete, J.M.; Ortega, F.J.; Ricart, W.; Fernández-Real, J.M. Lactoferrin increases 172ThrAMPK phosphorylation and insulin-induced p473SerAKT while impairing adipocyte differentiation. Int. J. Obes. 2009, 33, 991–1000.
  86. Kaczmarek, N.; Jamka, M.; Walkowiak, J. An association of selected polymorphisms of the lactoferrin gene and genes for lactoferrin receptors in the prevalence of metabolic disorders in obese subjects. Pol. Merkur. Lekarski. 2020, 48, 120–123.
  87. Mayeur, S.; Spahis, S.; Pouliot, Y.; Levy, E. Lactoferrin, a Pleiotropic Protein in Health and Disease. Antioxid. Redox Signal. 2016, 24, 813–836.
  88. Sadeghi, O.; Milajerdi, A.; Siadat, S.D.; Keshavarz, S.A.; Sima, A.R.; Vahedi, H.; Adibi, P.; Esmaillzadeh, A. Effects of soy milk consumption on gut microbiota, inflammatory markers, and disease severity in patients with ulcerative colitis: A study protocol for a randomized clinical trial. Trials 2020, 21, 565.
  89. Yang, Z.; Jiang, R.; Chen, Q.; Wang, J.; Duan, Y.; Pang, X.; Jiang, S.; Bi, Y.; Zhang, H.; Lönnerdal, B.; et al. Concentration of Lactoferrin in Human Milk and Its Variation during Lactation in Different Chinese Populations. Nutrients 2018, 10, 1235.
  90. Weimer, K.E.D.; Roark, H.; Fisher, K.; Cotten, C.M.; Kaufman, D.A.; Bidegain, M.; Permar, S.R. Breast Milk and Saliva Lactoferrin Levels and Postnatal Cytomegalovirus Infection. Am. J. Perinatol. 2020, 38, 1070–1077.
  91. Gleerup, H.S.; Jensen, C.S.; Høgh, P.; Hasselbalch, S.G.; Simonsen, A.H. Lactoferrin in cerebrospinal fluid and saliva is not a diagnostic biomarker for Alzheimer’s disease in a mixed memory clinic population. EBioMedicine 2021, 67, 103361.
  92. Zhang, Y.; Lu, C.; Zhang, J. Lactoferrin and Its Detection Methods: A Review. Nutrients 2021, 13, 2492.
  93. Ramenzoni, L.L.; Hofer, D.; Solderer, A.; Wiedemeier, D.; Attin, T.; Schmidlin, P.R. Origin of MMP-8 and Lactoferrin levels from gingival crevicular fluid, salivary glands and whole saliva. BMC Oral Health 2021, 21, 385.
  94. Rosa, L.; Lepanto, M.S.; Cutone, A.; Ianiro, G.; Pernarella, S.; Sangermano, R.; Musci, G.; Ottolenghi, L.; Valenti, P. Lactoferrin and oral pathologies: A therapeutic treatment. Biochem. Cell Biol. 2021, 99, 81–90.
  95. Sangermano, R.; Pernarella, S.; Straker, M.; Lepanto, M.S.; Rosa, L.; Cutone, A.; Valenti, P.; Ottolenghi, L. The treatment of black stain associated with of iron metabolism disorders with lactoferrin: A litterature search and two case studies. Clin. Ter. 2019, 170, e373–e381.
  96. Artym, J.; Zimecki, M. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Biomedicines 2021, 9, 1940.
  97. Superti, F.; De Seta, F. Warding Off Recurrent Yeast and Bacterial Vaginal Infections: Lactoferrin and Lactobacilli. Microorganisms 2020, 8, 130.
  98. Moreau, M.C.; Duval-Iflah, Y.; Muller, M.C.; Raibaud, P.; Vial, M.; Gabilan, J.C.; Daniel, N. Effect of orally administered bovine lactoferrin and bovine IgG on the establishment of Escherichia coli in the digestive tract of gnotobiotic mice and human newborn infants. Ann. Microbiol. (Paris) 1983, 134B, 429–441.
  99. Hao, Y.; Wang, J.; Teng, D.; Wang, X.; Mao, R.; Yang, N.; Ma, X. A prospective on multiple biological activities of lactoferrin contributing to piglet welfare. Biochem. Cell Biol. 2021, 99, 66–72.
  100. Nguyen, D.N.; Jiang, P.-P.; Stensballe, A.; Bendixen, E.; Sangild, P.T.; Chatterton, D.E. Bovine lactoferrin regulates cell survival, apoptosis and inflammation in intestinal epithelial cells and preterm pig intestine. J. Proteom. 2016, 139, 95–102.
  101. Nguyen, D.N.; Li, Y.; Sangild, P.T.; Bering, S.B.; Chatterton, D.E.W. Effects of bovine lactoferrin on the immature porcine intestine. Br. J. Nutr. 2013, 111, 321–331.
  102. Garcia, C.; Duan, R.D.; Brévaut-Malaty, V.; Gire, C.; Millet, V.; Simeoni, U.; Bernard, M.; Armand, M. Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: An overview. Cell. Mol. Biol. 2013, 59, 108–131.
  103. Legrand, D.; Pierce, A.; Elass, E.; Carpentier, M.; Mariller, C.; Mazurier, J. Lactoferrin Structure and Functions. Bioact. Compon. Milk 2008, 606, 163–194.
  104. Wang, B.; Timilsena, Y.P.; Blanch, E.; Adhikari, B. Lactoferrin: Structure, function, denaturation and digestion. Crit. Rev. Food Sci. Nutr. 2019, 59, 580–596.
  105. Kruzel, M.L.; Actor, J.K.; Radak, Z.; Bacsi, A.; Saavedra-Molina, A.; Boldogh, I. Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model. Innate Immun. 2009, 16, 67–79.
  106. Tursi, A.; Elisei, W.; Brandimarte, G.; Giorgetti, G.M.; Modeo, M.E.; Aiello, F. Effect of lactoferrin supplementation on the effectiveness and tolerability of a 7-day quadruple therapy after failure of a first attempt to cure Helicobacter pylori infection. Med. Sci. Monit. 2007, 13, CR187–CR190.
  107. Zhang, Z.; Lu, M.; Chen, C.; Tong, X.; Li, Y.; Yang, K.; Lv, H.; Xu, J.; Qin, L. Holo-lactoferrin: The link between ferroptosis and radiotherapy in triple-negative breast cancer. Theranostics 2021, 11, 3167–3182.
  108. Yin, C.M.; Wong, J.H.; Xia, J.; Ng, T.B. Studies on anticancer activities of lactoferrin and lactoferricin. Curr. Protein Pept. Sci. 2013, 14, 492–503.
  109. Arias, M.; Hilchie, A.L.; Haney, E.F.; Bolscher, J.G.M.; Hyndman, M.E.; Hancock, R.E.W.; Vogel, H.J. Anticancer activities of bovine and human lactoferricin-derived peptides. Biochem. Cell Biol. 2017, 95, 91–98.
  110. Ma, J.; Guan, R.; Shen, H.; Lu, F.; Xiao, C.; Liu, M.; Kang, T. Comparison of anticancer activity between lactoferrin nanoliposome and lactoferrin in Caco-2 cells in vitro. Food Chem. Toxicol. 2013, 59, 72–77.
  111. Abad, I.; Conesa, C.; Sánchez, L. Development of Encapsulation Strategies and Composite Edible Films to Maintain Lactoferrin Bioactivity: A Review. Materials 2021, 14, 7358.
  112. Aguilar-Pérez, K.M.; Avilés-Castrillo, J.I.; Medina, D.I.; Parra-Saldivar, R.; Iqbal, H.M.N. Insight Into Nanoliposomes as Smart Nanocarriers for Greening the Twenty-First Century Biomedical Settings. Front. Bioeng. Biotechnol. 2020, 8, 579536.
  113. Guan, R.; Ma, J.; Wu, Y.; Lu, F.; Xiao, C.; Jiang, H.; Kang, T. Development and characterization of lactoferrin nanoliposome: Cellular uptake and stability. Nanoscale Res. Lett. 2012, 7, 679.
  114. Liu, W.; Ye, A.; Liu, W.; Liu, C.; Singh, H. Stability during in vitro digestion of lactoferrin-loaded liposomes prepared from milk fat globule membrane-derived phospholipids. J. Dairy Sci. 2013, 96, 2061–2070.
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Subjects: Chemistry, Analytical
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Paweł Kowalczyk
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Katarzyna Kaczyńska
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Patrycja Kleczkowska
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Iwona Bukowska-Ośko
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Karol Kramkowski
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Dorota Sulejczak
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