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1.
Int J Mol Sci ; 23(14)2022 Jul 20.
Article in English | MEDLINE | ID: covidwho-1964013

ABSTRACT

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.


Subject(s)
Iron Overload , Animals , Benzoates/therapeutic use , Deferasirox/therapeutic use , Deferiprone , Deferoxamine/therapeutic use , Inflammation/complications , Inflammation/drug therapy , Iron/therapeutic use , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron Overload/etiology , Mammals , Pyridones/therapeutic use
2.
Int J Mol Sci ; 23(12)2022 Jun 16.
Article in English | MEDLINE | ID: covidwho-1963993

ABSTRACT

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a "magic bullet" drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.


Subject(s)
COVID-19 , Iron Overload , Adult , COVID-19/drug therapy , Deferiprone/therapeutic use , Humans , Iron/therapeutic use , Iron Chelating Agents/adverse effects , Iron Overload/chemically induced , Iron Overload/etiology , Pyridones/pharmacology , Pyridones/therapeutic use
3.
J Cell Mol Med ; 26(9): 2520-2528, 2022 05.
Article in English | MEDLINE | ID: covidwho-1769729

ABSTRACT

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.


Subject(s)
COVID-19 , Iron Overload , Thalassemia , COVID-19/complications , Female , Hospitals , Humans , Iron Overload/etiology , Male , Oxygen , Registries , Thalassemia/complications , Thalassemia/therapy
7.
Molecules ; 26(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1320599

ABSTRACT

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.


Subject(s)
Chelating Agents/chemistry , Deferoxamine/chemistry , Animals , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Chelating Agents/pharmacology , Chemistry, Pharmaceutical/methods , Electrochemistry/methods , Electrolytes , Humans , Hydrogen-Ion Concentration , Ions , Iron/metabolism , Iron Chelating Agents/chemistry , Iron Overload/drug therapy , Kinetics , Ligands , Metals/chemistry , Neoplasms/drug therapy , Potentiometry , SARS-CoV-2 , Temperature , Zirconium/chemistry
8.
Transfus Clin Biol ; 29(1): 70-74, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1317783

ABSTRACT

INTRODUCTION: Because of iron overload complications, thrombosis and infectious predisposition, patients with severe forms of thalassemia are likely to be at increased risk of COVID-19 complications. RESULTS: A national survey conducted during the year 2020 across the French reference centers for hemoglobinopathies identified 16 cases of COVID-19 confirmed by RT-PCR in beta-thalassemia patients. Their age ranged from 11 months to 60 years. 15 patients were transfusion-dependent and 6 were splenectomized. Concerning iron overload related complications, none had diabetes or cirrhosis and only one had experienced heart failure. All 4 pediatric patients were pauci-symptomatic during the viral episode. Three patients (41, 49 and 57 years old) developed COVID-19 pneumonia requiring oxygen therapy without the need for mechanical ventilation. Neutropenia (absolute neutrophils count <0.5 10 9/L) was observed in 2 patients receiving long-term treatment with hydroxycarbamide and deferiprone. No thrombosis event, organ failure or death occurred. All patients recovered. CONCLUSION: Severity of COVID-19 in this population of young and middle-aged patients appeared increased compared to the general population but remained mild to moderate as already described in the few series reported in the literature. Occurrence of adverse events related to chronic treatment administered in thalassemia disease may be favored by the infectious episode.


Subject(s)
COVID-19 , Iron Overload , Thalassemia , beta-Thalassemia , Child , Humans , Infant , Iron Overload/epidemiology , Iron Overload/etiology , Middle Aged , SARS-CoV-2 , beta-Thalassemia/complications , beta-Thalassemia/therapy
9.
Cells ; 10(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1223957

ABSTRACT

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Subject(s)
COVID-19/diagnosis , Iron Overload/etiology , Liver Failure/etiology , Liver/pathology , Severity of Illness Index , Adult , Aged , Antiviral Agents , Biopsy , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Female , Ferritins/analysis , Hepatocytes/cytology , Hepatocytes/pathology , Humans , Iron/analysis , Iron/metabolism , Iron Overload/mortality , Iron Overload/pathology , Iron Overload/therapy , Liver/cytology , Liver/metabolism , Liver Failure/mortality , Liver Failure/pathology , Liver Failure/therapy , Liver Function Tests , Male , Middle Aged , Mitochondria/pathology , Positive-Pressure Respiration , SARS-CoV-2/isolation & purification
11.
Acta Biomed ; 91(3): e2020013, 2020 09 07.
Article in English | MEDLINE | ID: covidwho-1068225

ABSTRACT

BACKGROUND: The COVID epidemic hit like a tsunami worldwide. At the time of its arrival in Italy, available literary data were meager, and most of them concerned its epidemiology. World Health Organization proposed guidelines in march 2020, a strategy of treatment has been developed, and a significant number of subsequent articles have been published to understand, prevent, and cure COVID patients. METHODS: From the observation of two patients, we performed a careful analysis of scientific literature to unearth the relation between COVID infection, clinical manifestations as pneumonia and thrombosis, and to find out why it frequently affects obese, diabetics, and elderly patients. RESULTS: The analysis shows that hepcidin could represent one of such correlating factors. Hepcidin is most elevated in older age, in non-insulin diabetics patients and in obese people. It is the final target therapy of many medicaments frequently used. Viral disease, and in particular SARS-CoV19, could induce activation of the hepcidin pathway, which in turn is responsible for an increase in the iron load. Excess of iron can lead to cell death by ferroptosis and release into the bloodstream, such as free iron, which in turn has toxic and pro-coagulative effects. CONCLUSIONS: Overexpression of hepcidin and iron overload might play a crucial role in COVID infection, becoming potential targets for treatment. Hepcidin could also be considered as a biomarker to measure the effectiveness of our treatments and the restoration of iron homeostasis the final intent. (www.actabiomedica.it).


Subject(s)
COVID-19 , Diabetes Mellitus , Iron Overload , Aged , Hepcidins , Humans , Italy , Obesity , SARS-CoV-2
12.
Acta Biomed ; 91(4): e2020138, 2020 11 05.
Article in English | MEDLINE | ID: covidwho-1059751

ABSTRACT

Clinical observations in concert with literary data demonstrate that detrimental complications of COVID19-induced pathology (acute respiratory distress syndrome, multi-organ failure, Kawasaki-like disease etc.), could result from a disturbance of local iron homeostasis (FeH) in damaged tissues followed by abnormal coagulation in small vessels. To resolve these complications the local FeH needs to be recovered. Hepcidin, as a master regulator of FeH is both a major player in the recovery and a marker of an efficacy of the restoration. Therefore, both local and systemic hepcidin levels could serve as a dynamic marker of disease progression (the more hepcidin the worse is disease) and treatment efficacy (after iron homeostasis is recovered hepcidin disappears). On the contrast, artificial attempts to suppress hepcidin expression directly or application of hepcidin antagonists could be detrimental. Overall, more comprehensive research of hepcidin role in COVID-19 pathology is needed.


Subject(s)
COVID-19 , Diabetes Mellitus , Iron Overload , Aged , Friends , Hepcidins , Humans , Obesity , SARS-CoV-2
13.
Biomed Pharmacother ; 136: 111228, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1033016

ABSTRACT

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.


Subject(s)
COVID-19/metabolism , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron/metabolism , Lactoferrin/therapeutic use , SARS-CoV-2 , Humans , Iron/blood , Iron/chemistry , Lactoferrin/pharmacology
14.
Immunol Res ; 68(4): 213-224, 2020 08.
Article in English | MEDLINE | ID: covidwho-651271

ABSTRACT

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.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections , Ferritins/blood , Iron Chelating Agents/therapeutic use , Iron Overload , Iron/blood , Pandemics , Pneumonia, Viral , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Humans , Iron Overload/blood , Iron Overload/drug therapy , Iron Overload/epidemiology , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , SARS-CoV-2
17.
Int J Infect Dis ; 97: 303-305, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-459066

ABSTRACT

The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on the premise that respiratory failure is the leading cause of mortality. However, mounting evidence links accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyper-ferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.


Subject(s)
Coronavirus Infections/pathology , Iron Overload/virology , Pneumonia, Viral/pathology , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Cytokine Release Syndrome/virology , Ferroptosis , Hepcidins/physiology , Humans , Inflammation , Iron/blood , Mitochondria/pathology , Mitochondria/physiology , Oxidative Stress , Pandemics , Pneumonia, Viral/mortality , SARS-CoV-2
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