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Despite recent advances in cancer therapy, current treatments, including radiotherapy, chemotherapy, and immunotherapy, although beneficial, present attendant side effects and long-term sequelae, usually more or less affecting quality of life of the patients. Indeed, except for most of the immunotherapeutic agents, the complete lack of selectivity between normal and cancer cells for radio- and chemotherapy can make them potential antagonists of the host anti-cancer self-defense over time. Recently, the use of nutraceuticals as natural compounds corroborating anti-cancer standard therapy is emerging as a promising tool for their relative abundance, bioavailability, safety, low-cost effectiveness, and immuno-compatibility with the host. In this review, we outlined the anti-cancer properties of Lactoferrin (Lf), an iron-binding glycoprotein of the innate immune defense. Lf shows high bioavailability after oral administration, high selectivity toward cancer cells, and a wide range of molecular targets controlling tumor proliferation, survival, migration, invasion, and metastasization. Of note, Lf is able to promote or inhibit cell proliferation and migration depending on whether it acts upon normal or cancerous cells, respectively. Importantly, Lf administration is highly tolerated and does not present significant adverse effects. Moreover, Lf can prevent development or inhibit cancer growth by boosting adaptive immune response. Finally, Lf was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors due to its ability to cross the blood–brain barrier, thus globally appearing as a promising tool for cancer prevention and treatment, especially in combination therapies.

Milk derivative bovine Lactoferrin (bLf), a multifunctional glycoprotein available in large quantities and recognized as safe, possesses high homology and identical functions with human Lactoferrin. There are numerous food supplements containing bLf which, however, can vary in its purity, integrity and, consequently, functionality. Here, we report on a clinical trial where bLf (100 mg two times/day) was orally administered before (Arm A) or during meals (Arm B) to pregnant women with hereditary thrombophilia and suffering from anemia of inflammation. A significant increase of the number of red blood cells (RBCs), hemoglobin (Hb), total serum iron (TSI) and serum ferritin (sFtn) levels, along with a significant decrease of interleukin-6 were detected after 30 days in Arm A, but not in Arm B, thus letting us to hypothesize that bLf inefficacy could be related to its degradation by digestive proteases. To verify this hypothesis, bLf was incubated in gastric juice collected before or after meals. An undigested or a digested profile was observed when bLf was incubated in gastric juice sampled before or after meals, respectively. These results can explain the beneficial effect observed when bLf is administered under fasting conditions, i.e. in the absence of active proteases.

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the aggregation of α-synuclein in Lewy bodies. Among the pathological mechanisms involved is the alteration of iron homeostasis, which promotes oxidative stress and neuronal damage. Despite therapeutic advances, today, no treatment is available to modify the course of the disease. In this study, we investigated for the first time the neuroprotective potential of bovine lactoferrin (bLf) in both its Native (Nat-) and Holo forms, using rotenone-treated N1E-115 cells to mimic PD phenotype. The results showed that the Nat-bLf was more effective than Holo-bLf in counteracting rotenone-induced cytotoxicity and neurite retraction, preserving neuronal morphology and promoting neuritogenesis, as evidenced by increased β3-Tubulin and Growth-Associated Protein-43 markers (GAP-43). Both forms of bLf preserved Tyrosine Hydroxylase (TH) levels, crucial for dopamine synthesis, reduced the DNA damage marker γ-H2Ax and prevented rotenone-induced downregulation of Divalent Metal Transporter-1 (DMT-1) and Ferroportin (Fpn), key proteins involved in iron uptake and release, thereby limiting intracellular iron accumulation. Notably, only Nat-bLf reduced the levels of α-synuclein and markers of oxidative damage. Conversely, Holo-bLf exhibited pro-oxidant effects and increased α-synuclein accumulation even in absence of rotenone. Overall, these results highlight the differential neuroprotective effects of both Nat- and Holo-form, resulting from their distinct iron saturation level and their ability to modulate protein expression, with the native form emerging as a promising candidate for therapeutic strategies to counteract PD-associated neurodegeneration.

In the last 20 years, several new genes and proteins involved in iron metabolism in eukaryotes, particularly related to pathological states both in animal models and in humans have been identified, and we are now starting to unveil at the molecular level the mechanisms of iron absorption, the regulation of iron transport and the homeostatic balancing processes. In this review, we will briefly outline the general scheme of iron metabolism in humans and then focus our attention on the cellular iron export system formed by the permease ferroportin and the ferroxidase ceruloplasmin. We will finally summarize data on the role of the iron binding protein lactoferrin on the regulation of the ferroportin/ceruloplasmin couple and of other proteins involved in iron homeostasis in inflamed human macrophages.

Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.

Human lactoferrin (hLf), an 80-kDa multifunctional iron-binding cationic glycoprotein, is constitutively secreted by exocrine glands and by neutrophils during inflammation. hLf is recognized as a key element in the host immune defense system. The and experiments are carried out with bovine Lf (bLf), which shares high sequence homology and identical functions with hLf, including anti-inflammatory activity. Here, in \"pure\" M1 human macrophages, obtained by stimulation with a mixture of 10 pg/ml LPS and 20 ng/ml IFN-γ, as well as in a more heterogeneous macrophage population, challenged with high-dose of LPS (1 µg/ml), the effect of bLf on the expression of the main proteins involved in iron and inflammatory homeostasis, namely ferroportin (Fpn), membrane-bound ceruloplasmin (Cp), cytosolic ferritin (Ftn), transferrin receptor 1, and cytokines has been investigated. The increase of IL-6 and IL-1β cytokines, following the inflammatory treatments, is associated with both upregulation of cytosolic Ftn and downregulation of Fpn, membrane-bound Cp, and transferrin receptor 1. All these changes take part into intracellular iron overload, a very unsafe condition leading to higher host susceptibility to infections as well as iron deficiency in the blood and anemia of inflammation. It is, therefore, of utmost importance to counteract the persistence of the inflammatory status to rebalance iron levels between tissues/secretions and blood. Moreover, levels of the antiinflammatory cytokine IL-10 were increased in cells treated with high doses of LPS. Conversely, IL-10 decreased when the LPS/IFN-γ mix was used, suggesting that only the inflammation triggered by LPS high doses can switch on an anti-inflammatory response in our macrophagic model. Here, we demonstrate that bLf, when included in the culture medium, significantly reduced IL-6 and IL-1β production and efficiently prevented the changes of Fpn, membrane-bound Cp, cytosolic Ftn, and transferrin receptor 1 in \"pure\" M1 macrophages, as well as in the more heterogeneous macrophage population. In addition, the decrease of IL-10 induced by the LPS/IFN-γ mix was counteracted by bovine lactoferrin. Several drugs capable of modulating macrophagic phenotypes are emerging as attractive molecules for treating inflammation, and in this sense, bovine lactoferrin is no exception.

Aberrant sialylation has been associated with many types of tumors, characterized by aggressiveness and undifferentiated state. However, not exhaustive investigations have been performed on the sialylation status in glioblastoma multiforme (GBM), the most common primary and lethal malignant brain tumor in humans. Hence, in this study we performed a comprehensive characterization of the sialylation status in GBM evaluating specific sialyltransferases and various types of sialic acids (Sias) in different GBM cell lines. First, through in silico analysis we showed that the sialyltransferases ST6GAL1, ST3GAL2 and ST8SIA4 are significantly up-regulated in GBM tissues and related to lower patient survival. Then, we evaluated the expression levels of these sialyltransferases and their related Sias and observed a high variability among the different GBM cell lines. In addition, using the pan-sialyltransferase inhibitor 3-Fax, we highlighted the role of sialylation in some of the main oncogenic properties of GBM. Indeed, a significant reduction in mobility and migration capacity along with increased adhesiveness of GBM cells was observed upon sialyltransferases inhibition. Our findings showed that aberrant expression of different Sias types is crucial for cell migration and adhesion ability of GBM cells, suggesting that Sias might represent biomarkers for GBM and be useful to design innovative therapeutic strategies.

Background: Salivary gland tumors are relatively rare neoplasms, comprising approximately 3–6% of all head and neck tumors. Parotid gland carcinoma (PGC) represents approximately 70–80% of all salivary gland malignancies. Treatment strategies depend on tumor histology, stage, and molecular characteristics, with surgical resection and adjuvant radiotherapy being the mainstays of treatment for localized disease. Conversely, in advanced stages, therapeutic approaches, including chemotherapy and targeted agents, are more challenging. Methods: We present a case report of a 60-year-old patient with hepatic and nodal metastases of parotid gland carcinoma HER2+ who received dual blockade with Pertuzumab and trastuzumab (PH) with addition of Docetaxel, with the aim of highlighting the management and treatment outcomes. Results: Our patient received 4 cycles of chemotherapy and PH with near-complete response. After lymph node dissection (level I–IV) with primitive tumor resection and radiosurgery on the residual liver metastases, currently she continues treatment as maintenance. Conclusions: Based on the patient’s overall condition and response to current treatment, the oncology team ought to consider further targeted therapies, radiotherapy, or surgery as future therapeutic options.

Ferroportin (Fpn), a ferrous iron Fe(II) transporter responsible for the entry of iron into plasma, is regulated post‐translationally through internalization and degradation following binding of the hormone hepcidin. Cellular iron export is impaired in mice and humans with aceruloplasminemia, an iron overload disease due to mutations in the ferroxidase ceruloplasmin (Cp). In the absence of Cp Fpn is rapidly internalized and degraded. Depletion of extracellular Fe(II) by the yeast ferroxidase Fet3p or iron chelators can maintain cell surface Fpn in the absence of Cp. Iron remains bound to Fpn in the absence of multicopper oxidases. Fpn with bound iron is recognized by a ubiquitin ligase, which ubiquitinates Fpn on lysine 253. Mutation of lysine 253 to alanine prevents ubiquitination and maintains Fpn‐iron on cell surface in the absence of ferroxidase activity. The requirement for a ferroxidase to maintain iron transport activity represents a new mechanism of regulating cellular iron export, a new function for Cp and an explanation for brain iron overload in patients with aceruloplasminemia.

Ferritin is a cytosolic molecule comprised of subunits that self‐assemble into a nanocage capable of containing up to 4500 iron atoms. Iron stored within ferritin can be mobilized for use within cells or exported from cells. Expression of ferroportin (Fpn) results in export of cytosolic iron and ferritin degradation. Fpn‐mediated iron loss from ferritin occurs in the cytosol and precedes ferritin degradation by the proteasome. Depletion of ferritin iron induces the monoubiquitination of ferritin subunits. Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome. Specific mammalian machinery is not required to extract iron from ferritin. Iron can be removed from ferritin when ferritin is expressed in Saccharomyces cerevisiae , which does not have endogenous ferritin. Expressed ferritin is monoubiquitinated and degraded by the proteasome. Exposure of ubiquitination defective mammalian cells to the iron chelator desferrioxamine leads to degradation of ferritin in the lysosome, which can be prevented by inhibitors of autophagy. Thus, ferritin degradation can occur through two different mechanisms.