A statistical downscaling approach for generating high spatial resolution health risk maps: a case study of road noise and ischemic heart disease mortality in Melbourne, Australia.

INTRODUCTION: Road traffic noise increases the risk of mortality from ischemic heart disease (IHD). Because noise is highly localized, high resolution maps of exposures and health outcomes are key to urban planning interventions that are informed by health risks. In Australia, publicly accessible IHD deaths data are only available at the coarse spatial aggregation level of local government area (LGA), in which about 130,000 people reside. Herein, we addressed this limitation of health data using statistical downscaling and generated environmental health risk maps for noise at the meshblock level (MB; ~ 90 people). METHODS: We estimated noise exposures at the MB level using a model of road traffic noise in Melbourne, Australia, from 2011. As recommended by the World Health Organization, a non-linear exposure-response function for traffic noise and IHD was used to calculate odds ratios for noise related IHD in all MBs. Noise attributable risks of IHD death were then estimated by statistically downscaling LGA-level IHD rates to the MB level. RESULTS: Noise levels of 80 dB were recorded in some MBs. From the given noise maps, approximately 5% of the population was exposed to traffic noise above the risk threshold of 55 dB. Maps of excess risk at the MB level identified areas in which noise levels and exposed populations are large. Attributable rates of IHD deaths due to noise were generally very low, but some were as high as 5-10 per 100,000, and in extremely noisy and populated MBs represented more than 8% excess risk of IHD death. We presented results as interactive maps of excess risk due to noise at the small neighbourhood scale. CONCLUSION: Our method accommodates low-resolution health data and could be used to inform urban planning and public health decision making for various environmental health concerns. Estimated noise related IHD deaths were relatively few in Melbourne in 2011, likely because road traffic is one of many noise sources and the current noise model underestimates exposures. Nonetheless, this novel computational framework could be used globally to generate maps of noise related health risks using scant health outcomes data.

Mortality burden attributable to exceptional PM2.5 air pollution events in Australian cities: A health impact assessment.

Background: People living in Australian cities face increased mortality risks from exposure to extreme air pollution events due to bushfires and dust storms. However, the burden of mortality attributable to exceptional PM2.5 levels has not been well characterised. We assessed the burden of mortality due to PM2.5 pollution events in Australian capital cities between 2001 and 2020. Methods: For this health impact assessment, we obtained data on daily counts of deaths for all non-accidental causes and ages from the Australian National Vital Statistics Register. Daily concentrations of PM2.5 were estimated at a 5 km grid cell, using a Random Forest statistical model of data from air pollution monitoring sites combined with a range of satellite and land use-related data. We calculated the exceptional PM2.5 levels for each extreme pollution exposure day using the deviation from a seasonal and trend loess decomposition model. The burden of mortality was examined using a relative risk concentration-response function suggested in the literature. Findings: Over the 20-year study period, we estimated 1454 (95 % CI 987, 1920) deaths in the major Australian cities attributable to exceptional PM2.5 exposure levels. The mortality burden due to PM2.5 exposure on extreme pollution days was considerable. Variations were observed across Australia. Despite relatively low daily PM2.5 levels compared to global averages, all Australian cities have extreme pollution exposure days, with PM2.5 concentrations exceeding the World Health Organisation Air Quality Guideline standard for 24-h exposure. Our analysis results indicate that nearly one-third of deaths from extreme air pollution exposure can be prevented with a 5 % reduction in PM2.5 levels on days with exceptional pollution. Interpretation: Exposure to exceptional PM2.5 events was associated with an increased mortality burden in Australia's cities. Policies and coordinated action are needed to manage the health risks of extreme air pollution events due to bushfires and dust storms under climate change.

Climate Change, Drought and Rural Suicide in New South Wales, Australia: Future Impact Scenario Projections to 2099.

Mental health problems are associated with droughts, and suicide is one of the most tragic outcomes. We estimated the numbers of suicides attributable to drought under possible climate change scenarios for the future years until 2099, based on the historical baseline period 1970-2007. Drought and rural suicide data from the Australian state of New South Wales (NSW) were analyzed for the baseline data period. Three global climate models and two representative concentration pathways were used to assess the range of potential future outcomes. Drought-related suicides increased among rural men aged 10-29 and 30-49 yrs in all modelled climate change scenarios. Rural males aged over 50 yrs and young rural females (10-29) showed no increased suicide risk, whereas decreased suicide rates were predicted for rural women of 30-49 and 50-plus years of age, suggesting resilience (according to the baseline historical relationship in those population sub-groups). No association between suicide and drought was identified in urban populations in the baseline data. Australian droughts are expected to increase in duration and intensity as climate change progresses. Hence, estimates of impacts, such as increased rural suicide rates, can inform mitigation and adaptation strategies that will help prepare communities for the effects of climate change.

Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition.

Selective targeting of elevated copper (Cu) in cancer cells by chelators to induce tumor-toxic reactive oxygen species (ROS) may be a promising approach in the treatment of glioblastoma multiforme (GBM). Previously, the Cu chelator di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) attracted much interest due to its potent anti-tumor activity mediated by the formation of a highly redox-active Cu-Dp44mT complex. However, its translational potential was limited by the development of toxicity in murine models of cancer reflecting poor selectivity. Here, we overcame the limitations of Dp44mT by incorporating it in new biomimetic nanoparticles (NPs) optimized for GBM therapy. Biomimetic design elements enhancing selectivity included angiopeptide-2 functionalized red blood cell membrane (Ang-M) camouflaging of the NPs carrier. Co-loading Dp44mT with regadenoson (Reg), that transiently opens the blood-brain-barrier (BBB), yielded biomimetic Ang-MNPs@(Dp44mT/Reg) NPs that actively targeted and traversed the BBB delivering Dp44mT specifically to GBM cells. To further improve selectivity, we innovatively pre-loaded GBM tumors with Cu. Oral dosing of U87MG-Luc tumor bearing mice with diacetyl-bis(4-methylthiosemicarbazonato)-copperII (Cu(II)-ATSM), significantly enhanced Cu-level in GBM tumor. Subsequent treatment of mice bearing Cu-enriched orthotopic U87MG-Luc GBM with Ang-MNPs@(Dp44mT/Reg) substantially prevented orthotopic GBM growth and led to maximal increases in median survival time. These results highlighted the importance of both angiopeptide-2 functionalization and tumor Cu-loading required for greater selective cytotoxicity. Targeting Ang-MNPs@(Dp44mT/Reg) NPs also down-regulated antiapoptotic Bcl-2, but up-regulated pro-apoptotic Bax and cleaved-caspase-3, demonstrating the involvement of the apoptotic pathway in GBM suppression. Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorders.

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling.

Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages. HuH7 hepcidin mRNA expression was determined using quantitative polymerase chain reaction (Q-PCR). Hepcidin promoter activity was measured using luciferase reporter constructs containing a 0.9 kb fragment of the wild-type human hepcidin promoter, and constructs containing mutations in bone morphogenetic protein (BMP)/SMAD4, signal transducer and activator of transcription 3 (STAT3), CCAAT/enhancer-binding protein (C/EBP), and E-box-responsive elements. Hepatic expression of bone morphogenetic proteins BMP2 and BMP6 and the BMP inhibitor noggin was determined using Q-PCR, and the protein expression of hemojuvelin (HJV), pSMAD 1/5/8, and SMAD4 was determined by western blotting. Following exposure to hypoxia or H(2)O(2), hepcidin mRNA expression and promoter activity increased in HuH7 cells monocultures but were decreased in HuH7 cells cocultured with THP-1 macrophages. This repression was attenuated by mutation of the BMP/SMAD4-response element, suggesting that modulation of SMAD signaling mediated the response to hypoxia. No changes in hepatocyte BMP2, BMP6 or noggin mRNA, or protein expression of HJV or pSMAD 1/5/8 were detected. However, treatment with hypoxia caused a marked decrease in nuclear and cytosolic SMAD4 protein and SMAD4 mRNA expression in cocultured HuH7 cells. Together these data indicate that hypoxia represses hepcidin expression through inhibition of BMP/SMAD signaling.

Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure.

Erythropoietin is produced by the kidney and stimulates erythropoiesis; however, in chronic renal disease its levels are reduced and patients develop anemia that is treatable with iron and recombinant hormone. The mechanism by which erythropoietin improves iron homeostasis is still unclear, but it may involve suppression of the iron regulatory peptide hepcidin and/or a direct effect on intestinal iron absorption. To investigate these possibilities, we used the well-established 5/6th nephrectomy rat model of chronic renal failure with or without human recombinant erythropoietin treatment. Monolayers of human intestinal Caco-2 cells were also treated with erythropoietin to measure any direct effects of this hormone on intestinal iron transport. Nephrectomy increased hepatic hepcidin expression and decreased intestinal iron absorption; these effects were restored to levels found in sham-operated rats on erythropoietin treatment of the rats with renal failure. In Caco-2 cells, the addition of erythropoietin significantly increased the expression of apical divalent metal transporter 1 (DMT1) and basolateral ferroportin and, consequently, iron transport across the monolayer. Taken together, our results show that erythropoietin not only exerts a powerful inhibitory action on the expression of hepcidin, thus permitting the release of iron from reticuloendothelial macrophages and intestinal enterocytes, but also acts directly on enterocytes to increase iron absorption.

Avoidable Mortality Attributable to Anthropogenic Fine Particulate Matter (PM2.5) in Australia.

Ambient fine particulate matter <2.5 µm (PM2.5) air pollution increases premature mortality globally. Some PM2.5 is natural, but anthropogenic PM2.5 is comparatively avoidable. We determined the impact of long-term exposures to the anthropogenic PM component on mortality in Australia. PM2.5-attributable deaths were calculated for all Australian Statistical Area 2 (SA2; n = 2310) regions. All-cause death rates from Australian mortality and population databases were combined with annual anthropogenic PM2.5 exposures for the years 2006-2016. Relative risk estimates were derived from the literature. Population-weighted average PM2.5 concentrations were estimated in each SA2 using a satellite and land use regression model for Australia. PM2.5-attributable mortality was calculated using a health-impact assessment methodology with life tables and all-cause death rates. The changes in life expectancy (LE) from birth, years of life lost (YLL), and economic cost of lost life years were calculated using the 2019 value of a statistical life. Nationally, long-term population-weighted average total and anthropogenic PM2.5 concentrations were 6.5 µg/m3 (min 1.2-max 14.2) and 3.2 µg/m3 (min 0-max 9.5), respectively. Annually, anthropogenic PM2.5-pollution is associated with 2616 (95% confidence intervals 1712, 3455) deaths, corresponding to a 0.2-year (95% CI 0.14, 0.28) reduction in LE for children aged 0-4 years, 38,962 (95%CI 25,391, 51,669) YLL and an average annual economic burden of $6.2 billion (95%CI $4.0 billion, $8.1 billion). We conclude that the anthropogenic PM2.5-related costs of mortality in Australia are higher than community standards should allow, and reductions in emissions are recommended to achieve avoidable mortality.

Activated macrophages induce hepcidin expression in HuH7 hepatoma cells.

BACKGROUND: Hepcidin is an iron regulatory peptide produced by the liver in response to inflammation and elevated systemic iron. Recent studies suggest that circulating monocytes and resident liver macrophages--Küpffer cells--may influence both basal and inflammatory expression of hepcidin. DESIGN AND METHODS: We used an in vitro co-culture model to investigate hepatocyte hepcidin regulation in the presence of activated THP1 macrophages. HuH7 hepatoma cells were co-cultured with differentiated THP1 macrophages for 24 h prior to the measurement of HuH7 hepcidin (HAMP) mRNA expression using quantitative polymerase chain reaction, and HAMP promoter activity using a luciferase reporter assay. Luciferase assays were performed using the wild type HAMP promoter, and constructs containing mutations in BMP/SMAD4, STAT3, C/EBP and E-BOX response elements. Neutralizing antibodies against interleukin-6, interleukin-1beta , and the bone morphogenetic protein inhibitor noggin were used to identify the macrophage-derived cytokines involved in the regulation of HAMP expression. RESULTS: Co-culturing HuH7 cells with differentiated THP1 cells induced HAMP promoter activity and endogenous HAMP mRNA expression maximally after 24 h. This induction was fully neutralized in the presence of an interleukin-1beta antibody, and fully attenuated by mutations of the proximal C/EBP or BMP/SMAD4 response elements. CONCLUSIONS: Our data suggest that the interleukin-1beta and bone morphogenetic protein signaling pathways are central to the regulation of HAMP expression by macrophages in this co-culture model.

Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells.

Hepcidin is thought to control iron metabolism by interacting with the iron efflux transporter ferroportin. In macrophages, there is compelling evidence that hepcidin directly regulates ferroportin protein expression. However, the effects of hepcidin on intestinal ferroportin levels are less conclusive. In this study, we compared the effects of hepcidin on iron transporter expression in the spleen and duodenum of mice treated with hepcidin over a 24- to 72-h period and observed a marked decrease in the expression of ferroportin in both duodenal enterocytes and splenic macrophages following treatment. Changes in transporter protein expression were associated with significant decreases in duodenal iron transport and serum iron. In THP-1 macrophages, ferroportin protein levels were decreased by 300 and 1000 nmol/L hepcidin. In contrast, ferroportin protein expression was unaltered in intestinal Caco-2 cells following exposure to hepcidin. However, iron efflux from Caco-2 cells was significantly inhibited in the presence of hepcidin, suggesting that the peptide could block ferroportin function in these cells. We conclude that hepcidin regulates the release of iron from both enterocytes and macrophages. However, taken together with our previous work, it is apparent that macrophages are more sensitive than enterocytes to a hepcidin challenge.

Single frequency bioelectrical impedance is a poor method for determining fat mass in moderately obese women.

BACKGROUND: The primary aim of weight loss intervention in obesity is the loss of fat mass (FM). Hence, determinations of changes in FM and fat free mass (FFM) during weight loss are of clinical value. The authors compared the clinical utility of SkinFold Thickness (SKF), tetrapolar bioelectrical impedance analysis (BIA) and a body mass index (BMI) based calculation, in determining changes in percentage of fat mass (delta%FM). METHODS: Using dual X-ray absorptiometry (DEXA) measurements of %FM as a standard, BIA, SKF and BMI were compared in 41 moderately obese women (BMI 30-35) before and after significant weight loss (-13.9 +/- 5.8 kg). RESULTS: When measuring fat mass loss, SKF was precise and accurate with a bias of +0.86 +/- 6.16 %, while the BMI-based estimation had a systematic bias of +6.36 +/- 6.04 % (r2 = 0.791, P < 0.001). BIA using the Lukaski formula had a bias of +5.22 % and limits of agreement that approached the magnitude of the measurement (+/- 20.82 %), thus providing no information. In contrast, BIA using the Segal formula had a systematic bias of +7.81% (r2 = 0.636, P < 0.001) and gave narrower limits of agreement (+/- 8.34 %). CONCLUSION: For measuring changes in %FM with weight loss, BIA has no clinical value using the Lukaski formula, and using the Segal formula BIA provided no additional information to that given by BMI. We show that BIA instrument variables confound the estimates of %FM achieved by the BMI component of the Lukaski and Segal formulas.

Systematic review of medium-term weight loss after bariatric operations.

BACKGROUND: Although bariatric surgery is known to be effective in the short term, the durability of that effect has not been convincingly demonstrated over the medium term (> 3 years) and the long term (> 10 years). The authors studied the durability of weight loss after bariatric surgery based on a systematic review of the published literature. METHODS: All reports published up to September, 2005 were included if they were full papers in refereed journals published in English, of outcomes after Roux-en-Y gastric bypass (RYGBP), and its hybrid procedures of banded bypass (Banded RYGBP) and longlimb bypass (LL-RYGBP), biliopancreatic diversion with or without duodenal switch (BPD+/-DS) or laparoscopic adjustable gastric banding (LAGB). All reports that had at least 100 patients at commencement, and provided > or = 3 years of follow-up data were included. RESULTS: From a total of 1,703 reports extracted, 43 reports fulfilled the entry criteria (18 RYGBP; 18 LAGB; 7 BPD). Pooled data from all the bariatric operations showed effective and durable weight loss to 10 years. Mean %EWL for standard RYGBP was higher than for LAGB at years 1 and 2 (67 vs 42; 67 vs 53) but not different at 3, 4, 5, 6 or 7 years (62 vs 55; 58 vs 55; 58 vs 55; 53 vs 50; and 55 vs 51). There was 59 %EWL for LAGB at 8 years, and 52 %EWL for RYGBP at 10 years. Both the BPD+/-DS and the Banded RYGBP appeared to show better weight loss than standard RYGBP and LAGB, but with statistically significant differences present at year 5 alone. The LL-RYGBP was not associated with improved %EWL. Important limitations include lack of data on loss to follow-up, failure to identify numbers of patients measured at each data point and lack of data beyond 10 years. CONCLUSIONS: All current bariatric operations lead to major weight loss in the medium term. BPD and Banded RYGBP appear to be more effective than both RYGBP and LAGB which are equal in the medium term.

Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves fenton-derived free radical generation.

PURPOSE: The development of novel and potent iron chelators as clinically useful antitumor agents is an area of active interest. Antiproliferative activity of chelators often relates to iron deprivation or stimulation of iron-dependent free radical damage. Recently, we showed that novel iron chelators of the di-2-pyridylketone isonicotinoyl hydrazone (PKIH) class have potent and selective antineoplastic activity (E. Becker, et al., Br. J. Pharmacol., 138: 819-30, 2003). In this study, we assessed the effects of the PKIH analogues on the redox activity of iron in terms of understanding their antitumor activity. EXPERIMENTAL DESIGN: We tested the PKIH analogues for their ability to promote iron-mediated ascorbate oxidation, benzoate hydroxylation, and plasmid degradation. Subsequent experiments assessed their ability to bind DNA, inhibit topoisomerase I, and cause DNA damage. To measure intracellular reactive oxygen species, we used the redox-sensitive probe, 2',7'-dichloro-fluorescein-diacetate, to measure intracellular PKIH-dependent redox activity. RESULTS: The PKIH analogues had relatively little effect on ascorbate oxidation in the presence of Fe(III) but stimulated benzoate hydroxylation and plasmid DNA degradation in the presence of Fe(II) and H2O2. These ligands could not inhibit DNA topoisomerase I or cause DNA damage in intact cells. PKIH markedly increased the intracellular generation of reactive oxygen species, and this was inhibited by catalase. This enzyme also decreased the antiproliferative effect of PKIH, indicating H2O2 played a role in its cytotoxic activity. CONCLUSIONS: Our results suggest that the antiproliferative effects of these chelators relates to intracellular iron chelation, followed by the stimulation of iron-mediated free radical generation via the so-formed iron complex.

Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311.

PURPOSE: Tumors are sensitive to iron (Fe) chelation therapy with the clinically used chelator desferrioxamine (DFO). Recently, the potent inhibitor of ribonucleotide reductase, Triapine, has entered clinical trials as an anticancer agent. This compound is a potential Fe chelator, but despite this, no investigations have examined its effect on cellular Fe metabolism. This is essential for understanding its mechanism of action and clinical effects. EXPERIMENTAL DESIGN: We compared the effect of Triapine with DFO, and also with the novel Fe chelator, 311, which shows marked antiproliferative activity. This latter ligand was relevant to compare, because it is tridentate like Triapine and shares structural similarity. We assessed the effects of chelators on proliferation, Fe uptake, Fe efflux, the expression of cell cycle control molecules, and iron-regulatory protein-RNA-binding activity. Redox activity was determined by ascorbate oxidation, benzoate hydroxylation, plasmid DNA degradation, and the precipitation of cellular DNA. These studies have been performed using several neuroepithelioma and neuroblastoma cell lines and a variety of normal cell types including fibroblasts, umbilical vein endothelial cells, skeletal muscle cells, monocyte-derived macrophages, and bone marrow stem cells. RESULTS: Triapine was twice as effective as DFO at mobilizing (59)Fe from prelabeled cells but was much less efficient than 311. In terms of preventing (59)Fe uptake from Tf, Triapine and DFO had similar activity, having far less efficacy than 311. All three of the chelators showed greater activity against the proliferation of neoplastic than of normal cells, the effect of 311 and Triapine being similar and these two chelators being significantly (P < 0.0001) more active than DFO. Complexation of Triapine with Fe had no appreciable effect on its antiproliferative activity, whereas addition of Fe totally inhibited the effects of DFO and 311. Furthermore, the Triapine Fe complex was shown to be redox active. CONCLUSION: The cytotoxic mechanism of action of Triapine was different from that of DFO and 311, with the combined action of Fe chelation and free radical generation being involved.

Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity.

The success of the iron (Fe) chelator desferrioxamine (DFO) in the treatment of beta-thalassemia is limited by its lack of bioavailability. The design and characterization of synthetic alternatives to DFO has attracted much scientific interest and has led to the discovery of orally active chelators that can remove pathological Fe deposits. However, chelators that access intracellular Fe pools can be toxic by either inhibiting Fe-containing enzymes or promoting Fe-mediated free radical damage. Interestingly, toxicity does not necessarily correlate with Fe-binding affinity or with chelation efficacy, suggesting that other factors may promote the cytopathic effects of chelators. In this review, we discuss the interactions of chelators and their Fe complexes with biomolecules that can lead to toxicity and tissue damage.

Interactions of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone class of chelators with iron and DNA: implications for toxicity in the treatment of iron overload disease.

Iron chelation therapy for the management of iron-overload disease is dominated by desferrioxamine (DFO). However, treatment using DFO is very arduous. Recently, novel Fe chelators of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone (PCIH) class have shown high chelation efficacy and the potential to replace DFO. A critical consideration in the design of alternatives to DFO is that the chelator forms a redox-inert Fe complex. In the present study, the participation of Fe complexes in redox reactions has been investigated. Ascorbate oxidation in the presence of Fe(III) or benzoate hydroxylation in the presence of Fe(II) was not enhanced by the PCIH analogues. However, redox-induced DNA strand breaks were observed with these ligands under highly oxidizing conditions in the presence of Fe(II) and hydrogen peroxide. Experiments then examined the interactions of the PCIH analogues with DNA, and this was found to be weak. Considering this, we suggest that under extreme conditions seen in the DNA-strand break assay, weak DNA-binding may potentiate the redox activity of the PCIH analogues. However, importantly, in contrast to naked plasmid DNA, DNA damage by these chelators using intact human cells was not significant. Collectively, our results support the potential of the PCIH analogues for the treatment of Fe overload.

Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues.

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate ( N, N, O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of theHPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe(II), with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of theHPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from theHPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of theseHPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.