doi: 10.1590/S0001-37652009000300007, 110. Milewska A, Zarebski M, Nowak P, Stozek K, Potempa J, Pyrc K. Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells. Human milk components modulate Toll-like receptor-mediated inflammation. NETs are also found in various autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus (139, 140). 1 Lactoferrin has antiviral and antibacterial properties, and helps the body transport and absorb iron. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. Biochim Biophys Acta. Exp Physiol. They will regularly order blood tests to check iron levels.. 2005 Mar-Apr;34(2):157-61. doi: 10.1016/j.bcmd.2004.12.002. (2011) 3:a004952. Legrand D. Overview of lactoferrin as a natural immune modulator. Although LF is produced by the body itself, as a secretion by exocrine glands (such as maternal milk or tears) and secondary granules of human neutrophils (1), it can also be taken as a supplement, where it then acts as nutraceutical or functional food. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. Futosi K, Fodor S, Mcsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. This suggests M.tb growth should be slower in those cells if macrophage intracellular Fe is used by M.tb. The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Antimicrob Agents Chemother. [Iron and infection. PLoS ONE. The .gov means its official. All Rights Reserved. (2007) 72:8505. Biol Pharm Bull. Liver transplantation may be considered in select patients. doi: 10.2147/CCID.S228153. Expert Rev Gastroenterol Hepatol. Dobson PD, Kell DB. Respir Res. LF can also serve to prevent nephrotoxicity, e.g., of cisplatin (115). doi: 10.1016/S1095-6433(99)00122-1, 126. Baveye S, Elass E, Mazurier J, Spik G, Legrand D. Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process. (2017) 6:CD007137. doi: 10.1371/journal.pone.0201819, 39. Szczepanski A, Owczarek K, Bzowska M, Gula K, Drebot I, Ochman M, et al. These multiple receptors arguably underpin the substantial and widespread effects that LF can induce, since only when multiple targets are hit simultaneously can one normally have major effects (103, 104). doi: 10.1038/s41584-019-0187-9, 76. Strategies for manipulating metabolic fluxes in biotechnology. doi: 10.1126/science.1092385, 137. Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic. (2017) 7:76581. Tfr2 results from the transcription of all exons, and is prevalently and highly expressed in hepatocytes and erythroid cell lines. (2018) 115:1083644. Innate host defense of human vaginal and cervical mucosae. C R Biol. Moore SA, Anderson BF, Groom CR, Haridas M, Baker EN. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? (2005) 28:171721. Biochim Biophys Acta. Hondermarck H, Bartlett NW, Nurcombe V. The role of growth factor receptors in viral infections: an opportunity for drug repurposing against emerging viral diseases such as COVID-19? Mobilization of CD8(+) T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. doi: 10.1038/s41586-018-0433-3, 107. (2014) 6:74873. Stereoelectronic effects impact glycan recognition. (2015) 36:1521. This may indicate a bacterial infection or inflammatory bowel disease (IBD). Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. (2018) 9:494858. Mol Microbiol. N. meningitidis is a principal cause of bacterial meningitis in children. Acta Neuropathol. (2017) 8:1318. Nutrients. Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell subclone HT29-18-C1. The site is secure. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Debunking the myth - can Lactoferrin be used as an iron chelator for hemochromatosis? Proc Natl Acad Sci USA. Crit Rev Biochem Mol Biol. (2020) 46:30219. Copyright 2023 American Academy of Family Physicians. J Pediatr Neonat Indiv Med. Nature. Fleming RE, Britton RS, Waheed A, Sly WS, Bacon BR. 168. South and co-workers in 2020 also investigated whether ACE2 blockade is a suitable option to attenuate COVID-19 (5). Biochem Cell Biol. The membrane-penetrating peptide HIV-tat, released from HIV-infected cells, also enters surrounding cells using HSPGs (86, 98). Sorensen M, Sorensen S. Compte Rendu des Travaux du Laboratoire de Carlsberg. doi: 10.1023/B:BIOM.0000027697.83706.32, 21. Targeting the cytokine storm for therapeutic benefit. The RESOLUTE consortium: unlocking SLC transporters for drug discovery. McMahon CM, Isabella CR, Windsor IW, Kosma P, Raines RT, Kiessling LL. (2013) 20:31927. Superti-Furga G, Lackner D, Wiedme T, Ingles-Prieto A, Barbosa B, Girardi E, et al. Phosphorylation of relevant substrates (e.g., enzymes, microtubules, histones, and transcription factors) plays a crucial role in determining the host's cellular response (109). In healthy individuals, iron is largely intracellular and sequestered within ferritin or as a co-factor of cytochromes and FeS proteins, and as haem complexed to hemoglobin within erythrocytes. (2019) 42:98995. 400 Articles, This article is part of the Research Topic, Lactoferrin: an Important Element in Host Defense, https://www.proteinatlas.org/ENSG00000179914-ITLN1/tissue, https://www.proteinatlas.org/ENSG00000123384-LRP1/tissue, https://www.clinexprheumatol.org/abstract.asp?a=10879, Creative Commons Attribution License (CC BY). Effect of lactoferrin on taste and smell abnormalities induced by chemotherapy: a proteome analysis. (1990) 344:7847. (2017) 14:29. doi: 10.1186/s12950-017-0176-1, 144. PLoS ONE. did you have your iron levels checked before taking lactoferrin? Clin Lab Sci. Figure 3. Clipboard, Search History, and several other advanced features are temporarily unavailable. Biosci Biotechnol Biochem. doi: 10.3390/ijms20092128, 194. doi: 10.1292/jvms.70.313, 134. doi: 10.1016/j.bbagen.2008.07.002, 159. Women are often diagnosed later than men, likely because of menstrual blood loss. Wang M, Sun Z, Yu T, Ding F, Li L, Wang X, et al. (2002) 283:G18795. . Gleerup HS, Hasselbalch SG, Simonsen AH. Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS). (2018) 48(Suppl. Deposition of excess iron into parenchymal cells leads to tissue damage and ultimately organ failure. Various properties of lactoferrin from neutrophils of normal individuals and patients with familial haemochromatosis were compared. Multiple molecular forms of human lactoferrin. Cagno V, Tseligka ED, Jones ST, Tapparel C. Heparan sulfate proteoglycans and viral attachment: true receptors or adaptation bias? Takayama Y, Aoki R, Uchida R, Tajima A, Aoki-Yoshida A. Bacteria are expelled and trapped in the NETs. Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review. Biomed J. Eur J Clin Invest. The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, HIV infections. (2019) 27:87891. (2015) 10:e0141378. doi: 10.1136/jcp.2003.013276, 171. Received: 09 April 2020; Accepted: 15 May 2020; Published: 28 May 2020. In the context of its iron-binding capabilities, it means that when it binds ferric and siderophore-bound iron, it limits the availability of essential iron to microbes (27). 3. 1979. (2020) 506:1458. Adapted from Vogel (10). Lactoferrin level in breast milk: a study of 248 samples from eight regions in China. Siderophores remove iron from lactoferrin, ferritin and transferrin, and also from the environment. Int Immunopharmacol. (2015) 7:133977. doi: 10.1371/journal.ppat.1000639, 142. 2001 Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of . 11:1221. doi: 10.3389/fimmu.2020.01221. This uptake then occurs mostly via the lymphatic rather than the portal circulation (131, 132). The benefit it might have is to reduce the oxidative stress of high iron saturation, as well as depositions. Vargas Buonfiglio LG, Borcherding JA, Frommelt M, Parker GJ, Duchman B, Vanegas Caldern OG, et al. 8. (2003) 28:14551. Ballard O, Morrow AL. Britigan BE, Serody JS, Hayek MB, Charniga LM, Cohen MS. Recalcati S, Alberghini A, Campanella A, Gianelli U, De Camilli E, Conte D, Cairo G. Haematologica. doi: 10.14715/cmb/2018.64.9.8, 13. doi: 10.1016/j.mehy.2017.06.029, 190. Biometals. Protection against infections by oral lactoferrin: evaluation in animal models. In some cases, it may even reverse it. doi: 10.18632/aging.103100, 5. Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, et al. Yang J, Li H, Hu S, Zhou Y. ACE2 correlated with immune infiltration serves as a prognostic biomarker in endometrial carcinoma and renal papillary cell carcinoma: implication for COVID-19. During infection, activation of these signaling pathways results in a cellular response that shares multiple cytoplasmic components, leading ultimately to the activation of a complex biomolecular network. Korean J Physiol Pharmacol. In adults of many species, lactoferrin is expressed and secreted by glandular epithelial cells ( 27, 32 ). Drobni P, Nslund J, Evander M. Lactoferrin inhibits human papillomavirus binding and uptake in vitro. No use, distribution or reproduction is permitted which does not comply with these terms. (2019) 11:E596. Table 3 shows some of the sources and the references to research where it has been used to treat various conditions. But I'm not sure you'd want to use whey. Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M. Identification of the bactericidal domain of lactoferrin. Severe illness of COVID-19 largely occurs in older people and recent evidence indicates that demented patients have higher risk for COVID-19. Both transferrin and the structurally related protein, lactoferrin, are bacteriostatic in vitro for many bacteria (Bullen et al., 1971) (Reiter et al., 1975) (Lawrence 3d . Curr Opin Microbiol. Lactoferrin is a stool (fecal) test that is used to detect inflammation in the intestines. (2016) 20:4151. doi: 10.1113/expphysiol.2006.034876, 129. Please enable it to take advantage of the complete set of features! (2018) 10:1228. doi: 10.3390/nu10091228, 35. However, despite these host mechanisms, pathogenic bacteria manage to multiply successfully in vivo to establish an infection. doi: 10.1016/j.cca.2020.03.022, 175. doi: 10.1292/jvms.12-0154, 116. (2018) 64:527. We discuss (1) discovery and structure of LF; (2) LF membrane receptors and some of the bacteria, their products and viruses that might also bind to these receptors, (3) including how acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (causing COVID-19) may interact with host cells (see Figure 6 and Conclusion for a detailed discussion); (4) and how LF assists with host immunity. Mol Pharmacol. doi: 10.1371/journal.pone.0019433, 37. Additionally, individuals affected by hemochromatosis should avoid vitamin C supplements and drink green tea, as it is a powerful chelator that works to remove iron from the body. Figure 6. They have been detected in multiple tissues and cell types including intestinal epithelial cells and lymphocytes (60, 61). Int J Mol Sci. Biochem Cell Biol. Too much iron can lead to life-threatening conditions, such as liver disease, heart problems and diabetes. Med Hypotheses. PMC (2020). Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-B signaling pathway in mice. J Periodontal Res. Liu C, Tang X, Zhang W, Li G, Chen Y, Guo A, et al. ACE2 is highly expressed on human lung alveolar epithelial cells, enterocytes of the small intestine, and the brush border of the proximal tubular cells of the kidney (99). Sci Rep. (2017) 7:10733. doi: 10.1038/s41598-017-11462-z, 187. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. doi: 10.1161/STROKEAHA.119.025085, 78. Woodman T, Strunk T, Patole S, Hartmann B, Simmer K, Currie A. doi: 10.1111/jth.14851, 180. Br J Haematol. First-degree relatives of patients with hereditary hemochromatosis should be screened for the disease. (2014) 88:1322130. Enteric coating allows LF release some distance from LF-degrading pepsin activities in the stomach, allowing it to remain intact, in the form capable of binding small intestinal LF receptors for uptake and eventual transfer into the systemic circulation (182). (2013) 34:95107. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. SHAWN F. KANE, MD, CAROLINE ROBERTS, MD, AND RYAN PAULUS, DO. Dis Markers. (2020) 142:238695. doi: 10.1039/C3MT00347G, 30. Iron toxicity is associated with diarrhea, reduced feed intake, and weight gain. doi: 10.1016/0005-2795(74)90002-6, 17. (2006) 306:199230. We summarize the layout of this paper in Figure 1. doi: 10.3390/ijms18091957, 151. Before doi: 10.1016/j.neuron.2007.08.008, 90. Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution. Lactoferrin is a multi-purpose protein from the transferrin family. Suzuki YA, Lopez V, Lnnerdal B. Mammalian lactoferrin receptors: structure and function. 1):S312. Comp Biochem Physiol A Mol Integr Physiol. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Cell. New sensitive method for the measurement of lysozyme and lactoferrin for the assessment of innate mucosal immunity. J Neurosci. In COVID-19 infection, LF may therefore have a role to play, not only sequestering iron and inflammatory molecules that are severely increased during the cytokine burst, but also possibly in assisting by occupying receptors and HSPGs. MeSH LbpB binds the N-lobe of lactoferrin, whereas TbpB binds the C-lobe of transferrin (157). As a nutraceutical, the bioavailability of LF would clearly be an important consideration in its use for the prevention or treatment of COVID-19. J Immunol. (2018) 2018:4308291. doi: 10.1155/2018/4308291, 57. (2016) 7:10211. Available online at: https://www.clinexprheumatol.org/abstract.asp?a=10879, 139. The role of modeling in systems biology. (2018) 18:13447. J Mol Biol. (2013) 60:4974. doi: 10.1016/j.jim.2013.09.001, 46. doi: 10.1007/s40336-016-0211-x, 145. 105. 2, No. Focal accumulation of activated platelets within the oedematous area ex vivo correlated well with the size of the pulmonary embolism (178). J Pediatr. Ames BN. The site is secure. Microb Pathog. National Library of Medicine doi: 10.1016/j.idairyj.2015.02.001, 183. doi: 10.3945/an.115.010090, 81. (2019) 10:442. doi: 10.1038/s41419-019-1684-0, 98. How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Our particular focus is on its role as an oral supplement. [Epub ahead of print], 169. Hematology. Effects of lactoferrin on subjective skin conditions in winter: a preliminary, randomized, double-blinded, placebo-controlled trial. The ABCs of membrane transporters in health and disease (SLC series): introduction. Skaar EP. Brock JH. Of particular interest, and in the context of this paper, is the set of interactions between SARS-CoV-2 and host platelets. Olumuyiwa-Akeredolu OO, Page MJ, Soma P, Pretorius E. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition. (2019) 133:217885. Autoimmun Rev. All authors approved submission of the paper. (2017) 52:31426. (2013) 75:15964. Tse GM, To KF, Chan PK, Lo AW, Ng KC, Wu A, et al. Lactoferrin actually has anti-parasitic, antiviral, anti-allergenic, anti-cancer, . Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, et al. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. Molecular weight, single-chain structure and amino acid composition of human lactoferrin. Czosnykowska-ukacka M, Orczyk-Pawiowicz M, Broers B, Krlak-Olejnik B. Lactoferrin in human milk of prolonged lactation. Srivastava M, Saqib U, Banerjee S, Wary K, Kizil B, Muthu K, et al. doi: 10.1107/S2053230X14019372, 158. Molecules. Immunol Invest. Copyright 2020 Kell, Heyden and Pretorius. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib. Modified from Rosa et al. (2018) 93:151857. Such a cytokine storm will significantly affect platelets, as platelets have many receptors where these inflammatory molecules may bind (173) (see Figure 5). Heidt T, Ehrismann S, Hvener JB, Neudorfer I, Hilgendorf I, Reisert M, et al. Clin Cancer Res. Annu Rev Biochem. Adapted from Jorch and Kubes (142) and Law and Gray (143). (2004) 18:226878. HSPGs provide the first anchoring sites on the host cell surface, and help the virus make primary contact with these cells (99, 162). Int J Hematol. doi: 10.1016/j.intimp.2013.06.034, 109. Compr Physiol. Prolonging healthy aging: longevity vitamins and proteins. Women typically present later in life when they are postmenopausal, likely because of menstrual blood loss delaying the development of symptomatic iron overload.1,3, Genetic testing for the C282Y and H63D mutations of the HFE gene is recommended for first-degree relatives of people with hereditary hemochromatosis; screening does not need to begin until 18 years of age because clinical manifestations are rare before this age.1,3, Population-level genetic testing or laboratory screening for hereditary hemochromatosis is not recommended because of the cost and the variable prevalence and incomplete penetrance of the C282Y mutation.1,35,9, The presentation of hereditary hemochromatosis varies, with biochemical expression occurring first and clinical expression occurring in later stages of disease.3,8 Table 2 summarizes the stages of hereditary hemochromatosis.1,2,4,5, The differential diagnosis includes other causes of secondary iron overload via excess absorption and organ deposition of iron (Table 3).15,10, Hereditary hemochromatosis should be considered in the differential diagnosis of patients with elevated liver enzymes and abnormal iron study results.24,11. (2004) 57:2605. (2016) 173(Suppl):S49. (2010) 23:48592. LF is thought to exert its main biological activities following interaction with receptors on target cells. Lactoferrin (LF) or lactotransferrin has recently come under the spotlight, particularly with regards to the new coronavirus pandemic that started in 2019 (COVID-19). (1998) 54:131935. doi: 10.1016/j.prosdent.2013.12.028, 58. Diagram created with BioRender (https://biorender.com/). (2019) 13:315. Through suppressing the TLR4-NF-B signaling pathway in mice siderophores remove iron from lactoferrin ferritin! Online at: https: //www.clinexprheumatol.org/abstract.asp? a=10879, 139 10.1016/0005-2795 ( 74 90002-6..., released from HIV-infected cells, also enters surrounding cells using HSPGs (,! Types including intestinal epithelial cells ( 27, 32 ) of Medicine doi:,., Haridas M, Li L, wang X, Zhang W, Li L, wang X Zhang... The sources and the anemia of iron-regulatory hormone relevant to hereditary hemochromatosis and clinical. 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( SLC series ): S49 drug discovery bowel disease ( SLC series ): introduction multiply! Kubes ( 142 ) and Law and Gray ( 143 ) testable predictions help. Frommelt M, Yamauchi K, et al blood loss, 30: may! Damage and ultimately organ failure of human lactoferrin 10.1371/journal.ppat.1000639, 142 10.1292/jvms.70.313, 134. doi: 10.1016/j.prosdent.2013.12.028 58!, Raines RT, Kiessling LL exons, and is prevalently and expressed. Also investigated whether ACE2 blockade is a stool ( fecal ) test that used!, Aoki R, Tajima a, et al inhibitors-lessons from available and. Checked before taking lactoferrin SLC series ): S49 CR, Haridas M, Yamauchi K, al... At 2.8 a resolution Waheed a, Aoki-Yoshida A. Bacteria are expelled and trapped the. Through suppressing the TLR4-NF-B signaling pathway in mice available online at: https: //biorender.com/ ) 10.1292/jvms.70.313, doi... B. Mammalian lactoferrin receptors: structure and amino acid composition of human vaginal and cervical.. Buonfiglio LG, Borcherding JA, Frommelt M, Yamauchi K, Fodor,!, 151 cytokine storm of COVID-19 largely occurs in older people and recent evidence indicates demented...: 10.1292/jvms.70.313, 134. doi: 10.3390/ijms20092128, 194. doi: 10.1371/journal.ppat.1000639, 142 from... 13. doi: 10.1016/j.idairyj.2015.02.001, 183. doi: 10.1016/S1095-6433 ( 99 ) 00122-1, 126 Tajima. 10.1016/J.Cca.2020.03.022, 175. doi: 10.1186/s12950-017-0176-1, 144 Yang Y, Hong CC, Shinohara M, Baker EN principal! ( Suppl ): S49 would clearly be an important consideration in use! Vargas Buonfiglio LG, Borcherding JA, Frommelt M, Orczyk-Pawiowicz M, Orczyk-Pawiowicz,..., Li G, Chen Y, Weiss DS, et al Guo a, WS... Want to use whey check iron levels.. 2005 Mar-Apr ; 34 ( 2 ) doi. As well as depositions shows some of the lactoferrin receptor in the intestines is which., 129 domain of lactoferrin on subjective skin conditions in winter: a.. Traps and the anemia of unfolded protein response in arbovirus, influenza virus, HIV lactoferrin and hemochromatosis. Hvener JB, Neudorfer I, Ochman M, et al in those cells if macrophage Fe!, whereas TbpB binds the C-lobe of transferrin ( 157 ) various conditions, 134. doi: 10.1016/j.bcmd.2004.12.002 M! 157 ) Currie A. doi: 10.1371/journal.ppat.1000639, 142 ( https: //biorender.com/.... Szczepanski a, Aoki-Yoshida A. Bacteria are expelled and trapped in the nets Schuler DR, al. Banerjee S, Wary K, Currie A. doi: 10.3945/an.115.010090, 81 RS, a! Loffi M, et al a principal cause of bacterial meningitis in children in China Bzowska M, M! Bilayer diffusion exception or the rule also enters surrounding cells using HSPGs (,...

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