Heme is essential for the survival of most organisms, despite the fact of being potentially toxic. This dual effect is due to the ability of the iron (Fe) atom contained within the protoporphyrin ...ring of the heme molecule to participate in redox reactions and exchange electrons with a variety of substrates. Therefore, the pro-oxidant reactivity of heme needs to be kept under control, an effect achieved by its incorporation into the heme pockets of hemoproteins, i.e. proteins required to exert vital biological functions in which heme acts as prosthetic group. The release of heme from hemoproteins and the participation of Fe in the Fenton reaction lead to the generation of unfettered oxidative stress and programmed cell death. Although further investigations would be required to elucidate the regulation of heme in the brain, this molecule appears to be critically involved in the pathogenesis of different neurodegenerative diseases, as heme accumulation or deficiency is associated with impaired brain activity and neuronal death. Thus, the aim of this review is to provide an overview on the importance of heme in the brain and the pathophysiologic consequences associated with its accumulation.
Iron Homeostasis in Health and Disease Gozzelino, Raffaella; Arosio, Paolo
International Journal of Molecular Sciences,
01/2016, Letnik:
17, Številka:
1
Journal Article, Book Review
Recenzirano
Odprti dostop
Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and ...diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload.
Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe(2+), carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords ...protection against programmed cell death. The mechanism underlying this cytoprotective effect relies on the ability of HO-1 to catabolize free heme and prevent it from sensitizing cells to undergo programmed cell death. This cytoprotective effect inhibits the pathogenesis of a variety of immune-mediated inflammatory diseases.
Iron is a critical element for most organisms, which plays a fundamental role in the great majority of physiological processes. So much so, that disruption of iron homeostasis has severe multi-organ ...impacts with the brain being particularly sensitive to such modifications. More specifically, disruption of iron homeostasis in the brain can affect neurophysiological mechanisms, cognition, and social behavior, which eventually contributes to the development of a diverse set of neuro-pathologies. This article starts by exploring the mechanisms of iron action in the brain and follows with a discussion on cognitive and behavioral implications of iron deficiency and overload and how these are framed by the social context. Subsequently, we scrutinize the implications of the disruption of iron homeostasis for the onset and progression of psychosocial disorders. Lastly, we discuss the links between biological, psychological, and social dimensions and outline potential avenues of research. The study of these interactions could ultimately contribute to a broader understanding of how individuals think and act under physiological and pathophysiological conditions.
Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the ...UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.
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•α-gal is expressed at the surface of Plasmodium sporozoites•Anti-α-gal Abs recognizing E. coli O86:B7 are protective against malaria•Anti-α-gal Abs are cytotoxic to Plasmodium sporozoites•Vaccination against α-gal confers sterile protection against malaria
Specific members of the gut microbiota induce antibodies that prevent malaria transmission through recognition of a glycan residue that is shared by the microbiota and the causative agent of malaria, the Plasmodium.
Renal control of disease tolerance to malaria Ramos, Susana; Carlos, Ana Rita; Sundaram, Balamurugan ...
Proceedings of the National Academy of Sciences - PNAS,
03/2019, Letnik:
116, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill ...Plasmodium. However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.
Severe malarial anemia (SMA) increases the morbidity and mortality of Plasmodium, the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. ...It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.
Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that ...the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circulating free heme released from hemoglobin during infection. Heme administration after low-grade infection in mice promoted tissue damage and severe sepsis. Free heme contributed to the pathogenesis of severe sepsis irrespective of pathogen load, revealing that it compromised host tolerance to infection. Development of lethal forms of severe sepsis after high-grade infection was associated with reduced serum concentrations of the heme sequestering protein hemopexin (HPX), whereas HPX administration after high-grade infection prevented tissue damage and lethality. Finally, the lethal outcome of septic shock in patients was also associated with reduced HPX serum concentrations. We propose that targeting free heme by HPX might be used therapeutically to treat severe sepsis.
Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be ...oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium-infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi (Pcc), wild-type (Hmox1⁺/⁺) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (Hmox1⁻/⁻) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc-infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc-infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc-infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.
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