Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury.

BACKGROUND: The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS: HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS: The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS: Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.

Hypoxia and hypoxia mimetics differentially modulate histone post-translational modifications.

Post-translational modifications (PTMs) to the tails of the core histone proteins are critically involved in epigenetic regulation. Hypoxia affects histone modifications by altering the activities of histone-modifying enzymes and the levels of hypoxia-inducible factor (HIF) isoforms. Synthetic hypoxia mimetics promote a similar response, but how accurately the hypoxia mimetics replicate the effects of limited oxygen availability on the levels of histone PTMs is uncertain. Here we report studies on the profiling of the global changes to PTMs on intact histones in response to hypoxia/hypoxia-related stresses using liquid chromatography-mass spectrometry (LC-MS). We demonstrate that intact protein LC-MS profiling is a relatively simple and robust method for investigating potential effects of drugs on histone modifications. The results provide insights into the profiles of PTMs associated with hypoxia and inform on the extent to which hypoxia and hypoxia mimetics cause similar changes to histones. These findings imply chemically-induced hypoxia does not completely replicate the substantial effects of physiological hypoxia on histone PTMs, highlighting that caution should be used in interpreting data from their use.

A nanocellulose-based colorimetric assay kit for smartphone sensing of iron and iron-chelating deferoxamine drug in biofluids.

The current work describes the development of a "nanopaper-based analytical device (NAD)", through the embedding of curcumin in transparent bacterial cellulose (BC) nanopaper, as a colorimetric assay kit for monitoring of iron and deferoxamine (DFO) as iron-chelating drug in biological fluids such as serum blood, urine and saliva. The iron sensing strategy using the developed assay kit is based on the decrease of the absorbance/color intensity of curcumin-embedded in BC nanopaper (CEBC) in the presence of Fe(III), due to the formation of Fe(III)-curcumin complex. On the other hand, releasing of Fe(III) from Fe(III)-CEBC upon addition of DFO as an iron-chelating drug, due to the high affinity of this drug to Fe(III) in competition with curcumin, which leads to recovery of the decreased absorption/color intensity of Fe(III)-CEBC, is utilized for selective colorimetric monitoring of this drug. The absorption/color changes of the fabricated assay kit as output signal can be monitored by smartphone camera or by using a spectrophotometer. The results of our developed sensor agreed well with the results from a clinical reference method for determination of Fe(III) concentration in human serum blood samples, which revealed the clinical applicability of our developed assay kit. Taken together, regarding the advantageous features of the developed sensor as an easy-to-use, non-toxic, disposable, cost-effective and portable assay kit, along with those of smartphone-based sensing, it is anticipated that this sensing bioplatform, which we name lab-on-nanopaper, will find utility for sensitive, selective and easy diagnosis of iron-related diseases (iron deficiency and iron overload) and therapeutic drug monitoring (TDM) of iron-chelating drugs in clinical analysis as well.

Iron Chelators Dictate Immune Cells Inflammatory Ability: Potential Adjuvant Therapy for IBD.

BACKGROUND: The importance of hemoproteins for life lies largely in their iron-mediated chemical properties. In the human body, there are about 4 g of iron, a precious resource preserved by sophisticated recycling mechanisms. Iron is also important for pathogen growth, so it is not surprising that immune cells developed mechanisms to reduce iron availability in cases of inflammation. In healthy conditions, macrophages degrade hemoproteins and export iron, while if inflammation develops, they retain cytoplasmic iron to reduce extracellular iron concentrations. Iron-rich macrophages possess a stronger inflammatory ability, which explains the chronic inflammatory response observed in states of iron overload. Inflammatory bowel syndromes are often characterized by intestinal blood loss and consequent anemia, but iron-supplementation therapies may exacerbate the inflammatory response. In chronically transfused patients iron overload is frequently observed; the iron can become toxic and in excess, even fatal if not treated with iron-chelating drugs. CONCLUSION: In the present review, we discuss the importance of iron homeostasis in states of health and inflammation, focusing on iron and iron-chelation treatment for IBD patients. Oral administration of natural ironchelating chemicals may be an effective adjuvant therapy for IBD patients, acting on numerous aspects of chronic inflammatory syndromes.

High brain iron in etiology of Alzheimer's disease and therapeutic approaches / 中国药理学通报

Excessive iron accumulation in the brain occurs in Alzheimer' s disease (AD) with oxidative stress,amyloid deposition,tau phosphorylation,and neuronal cell cycle regulatory failure,leading to apoptosis.Therefore,there is a direct link between iron metabolism and AD pathogenesis. The present review elaborates on high brain iron in etiology of AD and the development of iron-chelating therapy for AD,aiming at preventing or slowing down disease evolution.