Mechanisms of defence from Fe(II) toxicity in human intestinal Caco-2 cells

Natoli, Manuela; Felsani, Armando; Ferruzza, Simonetta; Sambuy, Yula; Canali, Raffaella; Scarino, Maria Laura

doi:10.1016/j.tiv.2009.06.016

Cited by 30 publications

(20 citation statements)

References 30 publications

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“…We want to emphasize that all adhesion, invasion and translocation assays were performed with bacteria that were pre-loaded with iron, but that the experiments themselves were performed under iron-limiting conditions. This was important to prevent bias in our data, as it has been reported that iron itself has the potential to damage the gut wall directly via generation of oxygen radicals [17], [30]. In our current study, Caco-2 cells and E12 cells were maintained under standard condition without any additional iron, which is different from the study design of Foster et al who showed that elevated iron status of enterocytes increased bacterial invasion [31].…”

Section: Discussionmentioning

confidence: 84%

Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface

et al. 2012

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Recent trials have questioned the safety of untargeted oral iron supplementation in developing regions. Excess of luminal iron could select for enteric pathogens at the expense of beneficial commensals in the human gut microflora, thereby increasing the incidence of infectious diseases. The objective of the current study was to determine the effect of high iron availability on virulence traits of prevalent enteric pathogens at the host-microbe interface. A panel of enteric bacteria was cultured under iron-limiting conditions and in the presence of increasing concentrations of ferric citrate to assess the effect on bacterial growth, epithelial adhesion, invasion, translocation and epithelial damage in vitro. Translocation and epithelial integrity experiments were performed using a transwell system in which Caco-2 cells were allowed to differentiate to a tight epithelial monolayer mimicking the intestinal epithelial barrier. Growth of Salmonella typhimurium and other enteric pathogens was increased in response to iron. Adhesion of S. typhimurium to epithelial cells markedly increased when these bacteria were pre-incubated with increasing iron concentration (P = 0.0001), whereas this was not the case for the non-pathogenic Lactobacillus plantarum (P = 0.42). Cellular invasion and epithelial translocation of S. typhimurium followed the trend of increased adhesion. Epithelial damage was increased upon incubation with S. typhimurium or Citrobacter freundii that were pre-incubated under iron-rich conditions. In conclusion, our data fit with the consensus that oral iron supplementation is not without risk as iron could, in addition to inducing pathogenic overgrowth, also increase the virulence of prevalent enteric pathogens.

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Section: Discussionmentioning

confidence: 84%

Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface

et al. 2012

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“…While its underlying causes remain uncertain, and do not seem to have a significant genetic component (Baranzini et al 2010; Oksenberg et al 2008; Ramagopalan et al 2008), ROS are certainly implicated (Adibhatla and Hatcher 2010), and antioxidant therapies may be useful (Mirshafiey and Mohsenzadegan 2009). It is at least plausible that part of the demyelination is caused by ROS and in particular hydroxyl radicals, and it is thus of much interest that iron dysregulation and/or deposition have indeed been implicated directly (Adams 1988; Bakshi et al 2000, 2001, 2002, 2008; Bermel et al 2005; Brass et al 2006a, b; Ceccarelli et al 2009, 2010; Chard and Miller 2009; Craelius et al 1982; Drayer et al 1987; Eissa et al 2009; Exley et al 2006; Filippi and Agosta 2009; Ge et al 2007; Grimaud et al 1995; Haacke et al 2005, 2009, 2010; Hammond et al 2008; He and Yablonskiy 2009; Khalil et al 2009; LeVine and Chakrabarty 2004; Neema et al 2007a, b, 2009a, b; Pirko et al 2009; Sayre et al 2005; Schenck and Zimmerman 2004; Simka and Rybak 2008; Singh and Zamboni 2009; Stankiewicz et al 2007; Tjoa et al 2005; Walter et al 2009; Zamboni 2006; Zivadinov and Bakshi 2004; Zivadinov and Minagar 2009). While the extent of causality of the iron dysregulation in MS is not yet established, it is highly pertinent that iron chelators have been shown to suppress disease progression in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (Bowern et al 1984; Mitchell et al 2007; Pedchenko and LeVine 1998).…”

Section: Multiple Sclerosismentioning

confidence: 99%

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

2010

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Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

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“…Disruption of TJs could be due to the cytokine secretion, such as TNF-α and IFN-γ, in cirrhosis patients 87 . Iron can be toxic to the intestines in that it increases cell monolayer permeability and causes partial delocalization of claudin-4 from the plasma membrane to an intracellular compartment 88 . Expression of claudin-2 is induced by iron-deficiency in rats’ duodenum 89 .…”

Section: Claudins Are Modulated In the Disease State Of Intestinesmentioning

confidence: 99%

Claudins in intestines

et al. 2013

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Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases, and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases.

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Mechanisms of defence from Fe(II) toxicity in human intestinal Caco-2 cells

Cited by 30 publications

References 30 publications

Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface

Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

Claudins in intestines

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