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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
5.
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
6.
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
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