Suicide gene therapy: a promising approach towards gene delivery

n/

Heavy metal ions in wines: meta-analysis of target hazard quotients reveal health risks

<p>Abstract</p> <p>Background</p> <p>Metal ions such as iron and copper are among the key nutrients that must be provided by dietary sources. Numerous foodstuffs have been evaluated for their contributions to the recommended daily allowance both to guide for satisfactory intake and also to prevent over exposure. In the case of heavy metal ions, the focus is often on exposure to potentially toxic levels of ions such as lead and mercury. The aim of this study is to determine target hazard quotients (THQ) from literature reports giving empirical levels of metal ions in table wines using the reference upper safe limit value. Contributions to the THQ value were calculated for seven metal ions along with total values for each wine.</p> <p>Results</p> <p>The THQ values were determined as ranges from previously reported ranges of metal ion concentrations and were frequently concerningly high. Apart from the wines selected from Italy, Brazil and Argentina, all other wines exhibited THQ values significantly greater than one indicating levels of risk. The levels of vanadium, copper and manganese had the highest impact on THQ measures. Typical potential maximum THQ values ranged from 50 to 200 with Hungarian and Slovakian wines reaching 300. THQ values for a sample of red and white wines were high for both having values ranging from 30 to 80 for females based on a 250 mL glass per day.</p> <p>Conclusion</p> <p>The THQ values calculated are concerning in that they are mainly above the safe level of THQ<1. It is notable that in the absence of upper safe limits, THQ values cannot be calculated for most metal ions, suggesting that further unaccountable risks are associated with intake of these wines.</p

Study on the effects of nitrilotriproprionic acid and 4,5-dihydroxy-1,3-benzene disulphonate on the fractionation of beryllium in human serum using graphite furnace atomic absorption spectrometry

<p>Abstract</p> <p>Background</p> <p>Occupational exposure to beryllium may cause Chronic Beryllium Disease (CBD), a lung disorder initiated by an electrostatic interaction with the MHC class II human leukocyte antigen (HLA). Molecular studies have found a significant correlation between the electrostatic potential at the HLA-DP surface and disease susceptibility. CBD can therefore be treated by chelation therapy. In this work, we studied the effect of two complexing agents, nitrilotriproprionic acid (NTP) and 4,5-dihydroxy-1,3-benzene disulphonate (Tiron), on the fractionation of beryllium in human serum analysed by graphite furnace atomic absorption spectrometry (GFAAS).</p> <p>Results</p> <p>We found the average serum beryllium concentration of fourteen non-exposed individuals to be 0.53 (± 0.14) μg l^-1, with 21 (± 3)% of the beryllium mass bound to the low molecular weight fraction (LMW), and 79 (± 3)% bound to the high molecular weight fraction (HMW). The addition of Tiron increased the beryllium mass in the HMW fraction, while NTP was not seen to have any influence on the fractionation of beryllium between the two fractions. NTP was, however, shown to complex 94.5% of the Be mass in the LMW fraction. The beryllium GFAAS detection limit, calculated as three times the standard deviation of 10 replicates of the lowest standard (0.05 μg L^-1), was 6.0 (± 0.2) ng L^-1.</p> <p>Conclusion</p> <p>The concentration of beryllium or its fractionation in human serum was not affected by sex or smoking habit. On average, three quarters of the beryllium in serum were found in the HMW fraction. Of the two ligands tested, only Tiron was effective in mobilising beryllium under physiological conditions, thus increasing the Be content in the HMW fraction.</p

Protective Role of Taurine against Arsenic-Induced Mitochondria-Dependent Hepatic Apoptosis via the Inhibition of PKCδ-JNK Pathway

BACKGROUND: Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway. METHODOLOGY/PRINCIPAL FINDINGS: Rats were exposed to NaAsO(2) (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO(2) (10 microM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCdelta and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCdelta is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO(2) exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As-induced oxidative stress and apoptosis. CONCLUSIONS/SIGNIFICANCE: Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKCdelta-JNK signalling pathways. Therefore taurine supplementation could provide a new approach for the reduction of hepatic complication due to arsenic poisoning

Chelators in Iron and Copper Toxicity

Purpose of Review Chelation therapy is used for diseases causing an imbalance of iron levels (for example haemochromatosis and thalassaemia) or copper levels (for example Menkes’ and Wilson’s diseases). Currently, most pharmaceutical chelators are relatively simple but often have side effects. Some have been taken off the market. This review attempts to find theory and knowledge required to design or find better chelators. Recent Findings Recent research attempting to understand the biological mechanisms of protection against iron and copper toxicity is reviewed. Understanding of molecular mechanisms behind normal iron/copper regulation may lead to the design of more sophisticated chelators. The theory of metal ion toxicity explains why some chelators, such as EDTA, which chelate metal ions in a way which exposes the ion to the surrounding environment are shown to be unsuitable except as a means of killing cancer cells. The Lewis theory of acids and bases suggests which amino acids favour the attachment of the hard/intermediate ions Fe2+, Fe3+, Cu2+ and soft ion Cu+. Non-polar amino acids will chelate the ion in a position not in contact with the surrounding cellular environment. The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators. Clearly, nature has developed proteins which are less restricted. Recent research on naturally produced chelators such as siderophores and phytochemicals show some promise as pharmaceuticals. Summary Although an understanding of natural mechanisms of Fe/Cu regulation continues to increase, the pharmaceutical chelators for metal overload diseases remain simple non-protein molecules. Natural and synthetic alternatives have been studied but require further research before being accepted

Metal Poisoning: Threat and Management

Exposure to toxic metals remains a wide spread occupational and environmental problems in world. Due to their widespread use in human activities such as industry, agriculture and even as medicine numerous health risks may be associated with exposure to these substances. Lead, arsenic and cadmium generally interferes with a number of body functions such as the haematopoietic system, central nervous system (CNS), liver and kidneys. Over the past few decades there have been growing awareness and concern that the toxic biochemical and functional effects are occurring at lower level of metal exposure than those that produce overt clinical and pathological signs and symptoms. Despite many years of research we are still far from an effective treatment of chronic heavy metal poisoning. The main therapeutic option for chronic metal poisoning relies in chelation therapy. Chelating agents are capable of linking together metal ions to form complex structures which can be easily excreted from the body. They have been used clinically as antidotes for acute and chronic poisoning. 2, 3-dimercaprol (BAL) has long been the mainstay of chelation therapy of lead or arsenic poisoning. Meso 2, 3, -dimercaptosuccinic acid (DMSA) has been tried successfully in animals as well as in few cases of human lead or arsenic poisoning. However, one of the major disadvantages of chelation with DMSA has been its inability to remove heavy metal from the intracellular sites because of its lipophobic nature. Further, it does not provide protection in terms of clinical/ biochemical recovery. A new trend in chelation therapy has emerged to use combined treatment. This includes use of structurally different chelating agents or a combination of an antioxidant and a chelator to provide better clinical/biochemical recovery in addition to mobilization of heavy metal form intracellular sites. The present review article attempts to provide update information about the current strategies being adopted for a safe, effective and specific treatment for toxic metals/ metalloid (lead, arsenic and cadmium)

Combined administration of selenium and meso-2, 3-dimercaptosuccinic acid on arsenic mobilization and tissue oxidative stress in chronic arsenic-exposed male rats

Objective : The present study describes the effect of selenium either alone or in combination with meso-2, 3-dimercaptosuccinic acid (DMSA) against chronic arsenic poisoning in rats. Materials and Methods : Male Wistar rats were exposed to 100 ppm sodium arsenite in drinking water for eight months and treated thereafter with DMSA (0.3 mmol/kg orally) either individually or in combination with selenium (Se, 6.3 or 12.6 µmol/kg, intraperitoneally) once daily for five days. The effects of these treatments in influencing the arsenic (As)-induced changes in heme synthesis, hepatic, renal or brain oxidative stress were evaluated along with the As concentration in blood and soft tissues. Results : Exposure to As significantly altered biochemical parameters related to the heme synthesis pathway, blood and organ (liver, kidney and brain) oxidative stress while increasing body As burden in animals. Treatment with DMSA alone significantly reduced the adverse effects related to most of these biochemical parameters as well as the As concentration in blood and tissues. On the other hand, co-administration of Se with DMSA had only limited additional beneficial effects (particularly tissue oxidative stress) over the individual effect of DMSA. Conclusion : The above results suggest that Se administration during chelation affected by other agents had some beneficial effects on oxidative stress with no major additional beneficial effect on arsenic depletion

Influence of zinc-saccharide complexes on some haematological parameters in rats

The effects of three recently synthesized zinc-saccharide complexes (zinc-fructose, zinc-galactose and zinc-glucose) on blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione (GSH), zinc-protoporphyrin (ZPP) and urinary delta-aminolevulinic acid (ALA) levels have been investigated to ascertain the utility of these complexes as zinc supplements and as preventive agents against lead intoxication in rats