Emerging Roles of the Iron Chelators in Inflammation.

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator.

Deferoxamine B is an outstanding molecule which has been widely studied in the past decade for its ability to bind iron and many other metal ions. The versatility of this metal chelator makes it suitable for a number of medicinal and analytical applications, from the well-known iron chelation therapy to the most recent use in sensor devices. The three bidentate hydroxamic functional groups of deferoxamine B are the centerpiece of its metal binding ability, which allows the formation of stable complexes with many transition, lanthanoid and actinoid metal ions. In addition to the ferric ion, in fact, more than 20 different metal complexes of deferoxamine b have been characterized in terms of their chemical speciation in solution. In addition, the availability of a terminal amino group, most often not involved in complexation, opens the way to deferoxamine B modification and functionalization. This review aims to collect and summarize the available data concerning the complex-formation equilibria in solutions of deferoxamine B with different metal ions. A general overview of the progress of its applications over the past decade is also discussed, including the treatment of iron overload-associated diseases, its clinical use against cancer and neurodegenerative disorders and its role as a diagnostic tool.

The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.

Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.

SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.