To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism.

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In Vitro Models.

SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactoferrins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory homeostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1ß and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19.

Lactoferrin in the Prevention and Treatment of Intestinal Inflammatory Pathologies Associated with Colorectal Cancer Development.

The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.