[Spatial Variation Characteristics, Influencing Factors, and Sources of Hydrogeochemical of Surface Water and Groundwater in Mountainous Area of Hutuo River].

Surface runoff has dropped sharply in the mountainous area of the Hutuo River, posing a huge challenge to the sustainable use of groundwater in the North China Plain (NCP). The Taihang Mountain area is the main recharge source area of groundwater in the NCP. An in-depth study of spatial variation characteristics, influencing factors, and sources of hydrogeochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River can facilitate a comprehensive understanding of regional water resource status and sustainable utilization of water resources. Based on isotopic, hydrogeochemical, and mathematical statistics methods, this study analyzed spatial variation of hydrochemical characteristics in surface water and groundwater and its sources and main controlling factors. The results showed that the river water, well water, and spring water were all recharged by atmospheric precipitation in the mountainous areas of the Hutuo River. Under the combined influence of natural factors and human factors, the hydrogeochemical characteristics of river, well, and spring water showed large spatial differences. On the whole, the hydrochemical types of mainstreams were relatively concentrated. In the upper and lower mining reach areas, the mainstream water chemical type was dominated by Ca·Mg-SO4·HCO3, whereas that in the natural vegetation area (middle reach:between Qingshui River and Longhua River) was dominated by Ca·Mg-HCO3·SO4. In the upper stream, the main hydrochemical type of the Yukou River and Ehe River tributaries was Ca·Mg-SO4·HCO3, which was consistent with that of the main stream. The main hydrochemical types of the Muma River and Qingshui River tributaries were Ca-HCO3, Ca·Mg-HCO3, and Ca·Mg-HCO3·SO4 in the midstream. The main hydrochemical types of the Mianhe River and Yehe River tributaries were Ca-SO4, Ca·Mg-SO4, and Ca·Mg-SO4·HCO3. Mineral dissolution was still the main controlling factor for the hydrochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River. The contribution rates were 69.86% and 18.84% for mineral dissolution and human activities, respectively. Therefore, in the future, water resource utilization in the upper reaches of the Hutuo River should not only consider the issue of water quantity but also a series of water environment problems such as nitrate pollution and mining pollution caused by human activities.

[Hydrochemical Characteristics and Factors of Surface Water and Groundwater in the Upper Yongding River Basin].

The Yongding River basin is an important water conservation and ecological barrier area in the Northwest of Hebei Province. Reduced runoff and deterioration of the water environment in this area have become increasingly prominent under the effects of climate change and intensive human activities. Clarifying the chemical characteristics and factors of surface water and groundwater in the upper Yongding River basin can provide data and support for the sustainable use of water resources. Stable isotopes of hydrogen and oxygen (δ2H and δ18O) were used to study the sources of surface water and groundwater. Mathematical statistics and hydrogeochemical methods were then used to analyze the regional hydrogeochemical processes and factors of surface water and groundwater. The results showed that precipitation was the main source of surface water and groundwater. Under the effects of natural factors and human activities, the Yang River and Sanggan River basins exhibited significant differences in surface water chemistry. The sub-basins were ranked by ion concentration as follows: Sanggan River>Yang River. The main cation and anions of the Sanggan River basin were Na+, Cl-, and SO42-, while in the Yang River basin, Ca2+ and HCO3- were the most common. The water chemistry of the Sanggan River exhibited greater variation than that of the Yang River. Surface water chemistry were mainly controlled by mineral dissolution and evaporation, but human activities were reflected in different sub-basins. Surface water in the Sanggan River basin was affected by industrial wastewater discharge, while that of the Yang River basin was affected by agricultural production and cities. However, the continuous increase of Cl- and SO42- concentrations, caused by industrial wastewater discharge and acid rain, was the limiting factor for sustainable use of surface water resources. In future, surface water in Sanggan River basin should be used with consideration to the effects of both total salinity and chemical composition of the water, while in Yang River, a focus should be placed on total salinity. The use of surface water resources in accordance with local conditions is an effective measure for the sustainable use of water resources and the restoration of groundwater levels in this region.

Glutathione and the intracellular labile heme pool.

One candidate for the cytosolic labile iron pool is iron(II)glutathione. There is also a widely held opinion that an equivalent cytosolic labile heme pool exists and that this pool is important for the intracellular transfer of heme. Here we describe a study designed to characterise conjugates that form between heme and glutathione. In contrast to hydrated iron(II), heme reacts with glutathione, under aerobic conditions, to form the stable hematin-glutathione complex, which contains iron(III). Thus, glutathione is clearly not the cytosolic ligand for heme, indeed we demonstrate that the rate of heme degradation is enhanced in the presence of glutathione. We suggest that the concentration of heme in the cytosol is extremely low and that intracellular heme transfer occurs via intracellular membrane structures. Should any heme inadvertently escape into the cytosol, it would be rapidly conjugated to glutathione thereby protecting the cell from the toxic effects of heme.

CN128: A New Orally Active Hydroxypyridinone Iron Chelator.

Deferoxamine, deferiprone, and deferasirox are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy, and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation, leading to the formation of a nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the log P value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of ß-thalassemia after regular blood transfusion.

Synthesis and iron chelating properties of hydroxypyridinone and hydroxypyranone hexadentate ligands.

Chelation therapy has become an important therapeutic approach for some diseases. In attempt to identify clinically useful chelators, four hexadentate ligands were synthesized by conjugating the corresponding bidentate ligands (3-hydroxypyridin-4-one (3,4-HOPO), 3-hydroxypyridin-2-one (3,2-HOPO), 1-hydroxypyridin-2-one (1,2-HOPO), and 3-hydroxypyran-4-one) each with a free amino group to a tripodal acid. Their pKa values and affinities for iron(iii) were investigated. The pFe3+ values of the hexadentate pyridinones 1 (3,4-HOPO), 3 (3,2-HOPO) and 4 (1,2-HOPO), and the pyranone 2 was found to follow the sequence 1 > 4 ≫ 3 > 2, which is different to the pFe3+ value sequence of the corresponding bidentate forms (3,4-HOPO ≫ 3,2-HOPO > 1,2-HOPO > 3-hydroxypyranone). Hexadentate 3,4-HOPOs and 1,2-HOPOs have the greatest potential as iron scavenging agents.

[Source of Nitrate in Surface Water and Shallow Groundwater Around Baiyangdian Lake Area Based on Hydrochemical and Stable Isotopes].

In order to study the source of nitrate in surface water and groundwater near a domestic sewage discharge river in the Baiyangdian watershed, including the Fuhe River and Baiyangdian Lake, shallow groundwater and deep groundwater samples were collected in July 2014.Water chemistry and stable isotopes (δ2 H and δ18O) were used to study the relationship between the surface water and groundwater. δ15 N was used to explore the source of nitrate. The results show that urban and rural domestic sewage discharge to Fuhe River and then experience evaporation. Shallow groundwater is affected by the Fuhe River, Baiyangdian Lake, and lateral recharge from groundwater in the Taihang Mountain area. There are 16.7% of shallow groundwater samples exceeds the NO3- threshold for drinking water according to the World Health Organization standard. Due to the effect of self-purification capacity, the NO3- mass concentration in the Fuhe River is higher in the upstream area than in the downstream area. Due the regional water flow from northwest to southeast, the NO3- mass concentration in the shallow groundwater is higher in the south bank area than in north bank area. The shallow groundwater near the Fuhe River and Baiyangdian Lake is recharged by surface water. In addition, soil, fertilizer, and point sources are also major sources for groundwater nitrate. Urban and rural residential living and agricultural production activities are the main reasons for surface water and groundwater nitrate.

The interaction of pyridoxal isonicotinoyl hydrazone (PIH) and salicylaldehyde isonicotinoyl hydrazone (SIH) with iron.

The interaction of pyridoxal isonicotinoyl hydrazone (PIH) and salicylaldehyde isonicotinoyl hydrazone (SIH), two important biologically active chelators, with iron has been investigated by spectrophotometric methods. High iron(III) affinity constants were determined for PIH, logß2=37.0 and SIH, logß2=37.6. The associated redox potentials of the iron complexes were determined using cyclic voltammetry at pH7.4 as +130mV (vs normal hydrogen electrode, NHE) for PIH and +136mV(vs NHE) for SIH. These redox potentials are much higher than those corresponding to iron chelators in clinical use, namely deferiprone, -620mV; desferasirox, -600mV and desferrioxamine, -468mV. Although the positive redox potentials of SIH and PIH are similar to that of EDTA, namely +120mV, the iron complexes of these two hydrazone chelators, unlike the iron complex of EDTA, do not redox cycle in the presence of vitamin C. These properties render PIH and SIH as excellent scavengers of iron, under biological conditions. Both SIH and PIH scavenge mononuclear iron(II) and iron(III) rapidly. These fast kinetic properties of the hydrazone-based chelators provide a ready explanation for the adoption of SIH in fluorescence-based methods for the quantification of cytosolic iron(II).

Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones - Attempted optimization of the orally active iron chelator, deferiprone.

A range of close analogues of deferiprone have been synthesised. The group includes mono-, di- and tri-methyl-3-hydroxy-4(1H)-pyridones. These compounds were found to possess similar pFe(3+) values to that of deferiprone, with the exception of the 2.5-dimethylated derivatives. Surprisingly the NH-containing hydroxy-4(1H)-pyridones were found to be marginally more lipophilic than the corresponding N-Me containing analogues. This same group are also metabolised less efficiently by Phase 1 hydroxylating enzymes than the corresponding N-Me analogues. As result of this study, three compounds have been identified for further investigation centred on neutropenia and agranulocytosis.

Copper(II) binding properties of hepcidin.

Hepcidin is a peptide hormone that regulates the homeostasis of iron metabolism. The N-terminal domain of hepcidin is conserved amongst a range of species and is capable of binding Cu(II) and Ni(II) through the amino terminal copper-nickel binding motif (ATCUN). It has been suggested that the binding of copper to hepcidin may have biological relevance. In this study we have investigated the binding of Cu(II) with model peptides containing the ATCUN motif, fluorescently labelled hepcidin and hepcidin using MALDI-TOF mass spectrometry. As with albumin, it was found that tetrapeptide models of hepcidin possessed a higher affinity for Cu(II) than that of native hepcidin. The log K 1 value of hepcidin for Cu(II) was determined as 7.7. Cu(II) binds to albumin more tightly than hepcidin (log K 1 = 12) and in view of the serum concentration difference of albumin and hepcidin, the bulk of kinetically labile Cu(II) present in blood will be bound to albumin. It is estimated that the concentration of Cu(II)-hepcidin will be less than one femtomolar in normal serum and thus the binding of copper to hepcidin is unlikely to play a role in iron homeostasis. As with albumin, small tri and tetra peptides are poor models for the metal binding properties of hepcidin.

Dual selective iron chelating probes with a potential to monitor mitochondrial labile iron pools.

Mitochondria-targeted peptides incorporating dual fluorescent and selective iron chelators have been designed as novel biosensors for the mitochondrial labile iron pool. The probes were demonstrated to specifically co-localize with mitochondria and their fluorescence emission was found to be sensitive to the presence of iron.

Design and synthesis of novel pegylated iron chelators with decreased metabolic rate.

BACKGROUND: Deferiprone has proved to be a successful iron selective chelator in a range of pathologies. However, its use is limited by rapid Phase II metabolism, necessitating the administration of large doses. In an attempt to modify metabolic rate of this class of compounds, a range of pegylated 3-hydroxypyridin-4-ones has been synthesized. EXPERIMENTAL: The synthetic route in which the polyethylene glycol counterparts are introduced to a protected pyran ring involves either a Williamson etherification reaction or direct addition leading to polyethylene glycol-containing precursors. RESULTS & DISCUSSION: The introduction of the pegylated substituent was found to lead to a relatively low rate of metabolism for some of the derivatives (6a, 6b, 8a and 8b), offering a possible improvement over deferiprone.

Hexadentate 3-hydroxypyridin-4-ones with high iron(III) affinity: design, synthesis and inhibition on methicillin resistant Staphylococcus aureus and Pseudomonas strains.

A range of hexadentate 3-hydroxypyridin-4-ones have been synthesized. These compounds were found to possess a high affinity for iron(III), with logK1 values of about 34 and pFe values over 30. Antimicrobial assays indicated that they can inhibit the growth of three clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) and three clinical isolates of Pseudomonas, suggesting that hexadentate 3-hydroxypyridin-4-ones have potential application in the treatment of wound infections.

Deferitazole, a new orally active iron chelator.

Following a systematic search of desferrithiocin analogs, a polyether derivative, deferitazole (formerly FBS0701), has entered into phase 1 and 2 clinical trials with promising biological properties. However, until now, detailed physicochemical properties of this chelator have not been reported. The compound displays a high affinity and selectivity for iron(III) as demonstrated by the log ß2 = 33.39 ± 0.03 and the pFe(3+) value of 22.3. Two equilibrating isomeric forms of the iron(III) complex exist under biological conditions. Deferitazole also binds the trivalent metals Al(III) and La(III) with high affinity; log ß2 values, 26.68 and 21.55 respectively. The affinity of deferitazole for divalent cations is somewhat lower, with the exception of Cu(II) which possesses a log ß2 value of 25.5; deferitazole scavenges iron from labile sources such as citrate and albumin with efficiencies comparable with those of other therapeutic iron chelators, including deferasirox, deferiprone and desferrioxamine. The Fe(III)(deferitazole)2 is stable under physiological conditions and does not redox cycle. The high affinity of deferitazole for iron(III) renders it unlikely that this chelator will lead to the redistribution of iron and consequently deferitazole shows considerable promise as a therapeutic iron(III) chelator.

Design, synthesis and biological evaluation of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates as potential photodynamic therapeutical agents.

5-Aminolaevulinic acid (ALA) prodrugs have been widely used in photodynamic therapy (PDT) as precursors to the natural photosensitizer, protoporphyrin IX (PpIX). The main disadvantage of this therapy is that ALA is poorly absorbed by cells due to its high hydrophilicity. In order to improve the therapeutical effect and induce higher yields of PpIX, a range of prodrugs of ALA conjugated to 3-hydroxypyridin-4-ones (HPO) were synthesized. Pharmacokinetic studies indicated that some of the ALA-HPO conjugates are more efficient than ALA for PpIX production in the human breast adenocarcinoma cell line (MDA-MB-468). The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, suggesting the potential application of the ALA-HPO conjugates in photodynamic therapy.

Mode of iron(III) chelation by hexadentate hydroxypyridinones.

Tripodal hexadentate hydroxypyridin-4-ones are increasingly utilised as iron(III) and gallium(III) ligands, their attachment to proteins being particularly useful for positron emission tomography (PET). A widely studied tripodal ligand NTA(BuHP)3, which is reported to form 1:1 iron(III) and gallium(III) complexes in aqueous, media forms 2:2 complexes under physiological conditions. This important difference has implications for both iron chelation therapy and PET imaging.

[Distribution Characteristics and Source of Fluoride in Groundwater in Lower Plain Area of North China Plain: A Case Study in Nanpi County].

There is an obvious regional contradiction between water resources and agricultural produce in lower plain area of North China, however, excessive fluorine in deep groundwater further limits the use of regional water resources. In order to understand the spatial distribution characteristics and source of F(-) in groundwater, study was carried out in Nanpi County by field survey and sampling, hydrogeochemical analysis and stable isotopes methods. The results showed that the center of low fluoride concentrations of shallow groundwater was located around reservoir of Dalang Lake, and centers of high fluoride concentrations were located in southeast and southwest of the study area. The region with high fluoride concentration was consistent with the over-exploitation region of deep groundwater. Point source pollution of subsurface drainage and non-point source of irrigation with deep groundwater in some regions were the main causes for the increasing F(-) concentrations of shallow groundwater in parts of the sampling sites. Rock deposition and hydrogeology conditions were the main causes for the high F(-) concentrations (1.00 mg x L(-1), threshold of drinking water quality standard in China) in deep groundwater. F(-) released from clay minerals into the water increased the F(-) concentrations in deep groundwater because of over-exploitation. With the increasing exploitation and utilization of brackish shallow groundwater and the compressing and restricting of deep groundwater exploitation, the water environment in the middle and east lower plain area of North China will undergo significant change, and it is important to identify the distribution and source of F(-) in surface water and groundwater for reasonable development and use of water resources in future.

Synthesis and characterizations of pyridazine-based iron chelators.

In an attempt to design ligands which require both a high iron(III) affinity and a low iron(II) affinity, the 3-hydroxypyridin-4-one structure has been modified to introduce an additional nitrogen atom in the pyridine ring to form a pyridazine. The target molecules were synthesized from a chlorine-substituted pyridazine using step-by-step methoxylations. A total of six 3- and 5-hydroxypyridazin-4(1H)-ones have been synthesized, with a methyl, ethyl or n-propyl group on the N1 of the pyridazine ring. In the reaction of the pyridazines with alkyl iodide, the presence of acetone drives the reaction to afford pyridazinones rather than the desired pyridaziniums. The pK(a) values of the free ligands, the stability constants of their iron(III) complexes and corresponding pFe(III) values demonstrate that this type of ligand has lower values when compared with those of deferiprone. The reduction potential values of the iron complexes obtained from cyclic voltammetry measurements, are used to determine the corresponding pFe(II) values. Although two compounds of the 20 series have marginally higher log ß3(Fe(III))/log ß3(Fe(II)) ratios than those of deferiprone, they possess pFe(III) values <20, indicating that this type of chelator is unlikely to be optimized into a useful therapeutic agent.

Pollution of intensively managed greenhouse soils by nutrients and heavy metals in the Yellow River Irrigation Region, Northwest China.

The present study aimed to assess the potential ecological risk of heavy metals and nutrient accumulation in polytunnel greenhouse soils in the Yellow River irrigation region (YRIR), Northwest China, and to identify the potential sources of these heavy metals using principal component analysis. Contents of available nitrogen (AN), phosphorus (AP), and potassium (AK) in the surface polytunnel greenhouse soils (0-20 cm) varied from 13.42 to 486.78, from 39.10 to 566.97, and from 21.64 to 1,156.40 mg kg(-1), respectively, as well as AP, soil organic matter (SOM) and AK contents tended to increase significantly at the 0-20- and 20-40-cm soil layers. Heavy metal accumulations occurred in the polytunnel greenhouse soils as compared to arable soils, especially at a depth of 20 cm where Cd, Zn and Cu contents were significantly higher than arable soil. Cd and As were found to be the two main polluting elements in the greenhouse soils because their contents exceeded the thresholds established for greenhouse vegetable production HJ333-2006 in China and the background of Gansu province. It has been shown that Cd, Cu, Pb and Zn at the 0-20-cm soil layer were derived mainly from agricultural production activities, whereas contents of Cr and Ni at the same soil layer were determined by 'natural' factors and As originated from natural sources, deposition and irrigation water.

Design, synthesis, and antimicrobial evaluation of hexadentate hydroxypyridinones with high iron(III) affinity.

A range of hexadentate 3-hydroxypyridin-4-ones (HPOs) with high affinity for iron(III) has been synthesized. The log stability constants of two HPO-iron complexes (logK1 ) were determined to be over 34, and pFe values of the two HPOs were determined to be over 31. Antimicrobial assay indicated that they are able to markedly inhibit the growth of both Gram-positive and Gram-negative bacteria. Compounds 14a and 14e were found to exhibit the strongest inhibitory activity against Staphyloccocus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, with MIC values of 8, 8, 16, and 8 µg/mL, respectively. These results indicate that hexadentate 3-hydroxypyridin-4-ones have potential application as antimicrobial agents, especially in the treatment of wound infection.