Juliana Ivanova

The role of cadmium in obesity and diabetes

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.

Crystal structures and spectral properties of new Cd(II) and Hg(II) complexes of monensic acid with different coordination modes of the ligand

AbstractThe single crystal X-ray structures and the spectroscopic properties of complexes of monensic acid (C36H62O11·H2O) with toxic metal ions of Cd(II) and Hg(II) are discussed. The cadmium(II) complex (1) is of composition [Cd(C36H61O11)2(H2O)2] and crystallizes in the monoclinic system (space group P2(1), Z = 2) with a = 12.4090(8), b = 24.7688(16), c = 14.4358(11) Å, β = 91.979(7)°. Two ligand monoanions are bound in a bidentate coordination mode to Cd(II) via the carboxylate and the primary hydroxyl oxygens occupying the equatorial plane of the complex. The axial positions of the inner coordination sphere of Cd(II) are filled by two water molecules additionally engaged in intramolecular hydrogen bonds. The Hg(II) complex (2), [Hg(C36H60O11)(H2O)], crystallizes in the orthorhombic system (space group P2(1)2(1)2(1), Z = 4) with a = 12.7316(2), b = 16.4379(3), c = 18.7184(4) Å. The monensic acid reacts with Hg(II) in a tetradentate coordination manner via both oxygen atoms of the carboxylate function and oxygens of two hydroxyl groups. The twofold negative charge of the ligand is achieved by deprotonation of carboxylic and secondary hydroxyl groups located at the opposite ends of the molecule. Hg(II) is surrounded by five oxygen atoms in a distorted square pyramidal molecular geometry.

Formation of nitroxyl and hydroxyl radical in solutions of sodium trioxodinitrate: Effects of pH and cytotoxicity

Despite its negative redox potential, nitroxyl (HNO) can trigger reactions of oxidation. Mechanistically, these reactions were suggested to occur with the intermediate formation of either hydroxyl radical (·OH) or peroxynitrite (ONOO–). In this work, we present further experimental evidence that HNO can generate ·OH. Sodium trioxodinitrate (Na2N2O3), a commonly used donor of HNO, oxidized phenol and Me2SO to benzene diols and ·CH3, respectively. The oxidation of Me2SO was O2-independent, suggesting that this process reflected neither the intermediate formation of ONOO– nor a redox cycling of transition metal ions that could initiate Fenton-like reactions. In solutions of phenol, Na2N2O3 yielded benzene-1,2-diol and benzene-1,4-diol at a ratio of 2:1, which is consistent with the generation of free ·OH. Ethanol and Me2SO, which are efficient scavengers of ·OH, impeded the hydroxylation of phenol. A mechanism for the hydrolysis of Na2N2O3 is proposed that includes dimerization of HNO to cis-hyponitrous acid (HO-N=N-OH) with a concomitant azo-type homolytic fission of the latter to N2 and ·OH. The HNO-dependent production of ·OH was with 1 order of magnitude higher at pH 6.0 than at pH 7.4. Hence, we hypothesized that HNO can exert selective toxicity to cells subjected to acidosis. In support of this thesis, Na2N2O3 was markedly more toxic to human fibroblasts and SK-N-SH neuroblastoma cells at pH 6.2 than at pH 7.4. Scavengers of ·OH impeded the cytotoxicity of Na2N2O3. These results suggest that the formation of HNO may be viewed as a toxicological event in tissues subjected to acidosis.

Distribution of lanthanoids, Be, Bi, Ga, Te, Tl, Th and U on the territory of Bulgaria using Populus nigra ‘Italica’ as an indicator

The concentrations of lanthanoids, Be, Bi,Ga, Te, Tl, Th and U have been determined using ICP-MS for 100 standardized samples of poplar leaves collected from the territory of Bulgaria. The investigated elements are log-normally distributed on the territory. Using cluster analysis of the analytical data the samples were grouped according soil type on which the plants are growing.

The tetraethylammonium salt of monensic acid—An antidote for subacute cadmium intoxication. A study using an ICR mouse model

In this study, the ability of the chelating agent monensic acid (administered as the tetraethylammonium salt) to reduce the cadmium (Cd) concentration in the kidneys, liver, heart, lungs, spleen and testes of Cd-intoxicated mice was investigated. Chelation therapy with the tetraethylammonium salt of monensic acid led to a significant decrease of the Cd concentration in all of the organs of the Cd-treated mice. This effect varied from 50% in the kidneys to 90% in the hearts of the sacrificed animals (compared to the Cd-treated controls). No redistribution of the toxic metal ions to the brain of the animals as a result of the detoxification with the chelating agent was observed. The detoxification of the animals with the antibiotic salt did not perturb the endogenous levels of copper (Cu) or zinc (Zn). The tetraethylammonium salt of monensic acid significantly ameliorated the Cd-induced total iron (Fe) depletion in the liver and spleen of Cd-treated mice. It also restored to control levels the values of transferrin-bound Fe and the total iron binding capacity (TIBC) of the plasma. These results imply that the tetraethylammonium salt of monensic acid could be an efficient antidote in cases of Cd-intoxication.

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin.

BackgroundThe natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in in vivo experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their in vitro complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).ResultsNew metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)2(H2O)2] (1) and [Pb(Sal)(NO3)] (2), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield 1. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex 2 consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.ConclusionThe formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.

Cobalt-Induced Changes in the Spleen of Mice from Different Stages of Development

Cobalt(II) accumulates in organs such as spleen, kidneys, heart, and liver. The aim of the present study was to investigate the effects of cobalt ethylenediamine tetraacetic acid (Co-EDTA) on spleen of developing mice. Pregnant BALB/c mice in late gestation were subjected to Co-EDTA treatment at daily doses of 75 or 125 mg/kg in drinking water, which continued until d 90 of the newborn pups. The newborn pups were sacrificed on d 18, 25, 30, 45, 60, and 90, which correspond to different stages of development. Spleens were excised, weighed, and processed for histological analysis. Spleen index (SI) was calculated as a ratio of spleen weight to body weight. Cobalt(II) bioaccumulation in spleen was determined using flame atomic absorption spectrometry (FAAS). Preliminary results showed that chronic treatment of mice with low- or high-dose Co-EDTA disturbed extramedullary hematopoiesis in the spleen. The number of megakaryocytes was reduced compared to controls. SI was also reduced in d 18 mice treated with low- or high-dose Co-EDTA. However, exposure to 75 mg/kg led to an increase of SI in all other experimental groups. FAAS analysis revealed significant cobalt(II) accumulation in spleen of treated mice. The Co(II) levels in spleens of d 18 mice were highest compared to other experimental groups, indicating that at this period mice are more sensitive to treatment. Exposure to cobalt-EDTA resulted in accumulation of Co(II) in spleen, altered SI, and hematopoiesis. Immature mice appear to be more sensitive to chronic treatment than adults.

Comparative assessment of the effects of salinomycin and monensin on the biodistribution of lead and some essential metal ions in mice, subjected to subacute lead intoxication.

In this study, we present a comparative assessment of the effects of two polyether ionophorous antibiotics (monensin and salinomycin) on the concentrations of lead (Pb), cooper (Cu), zinc (Zn) and iron (Fe) in the kidneys, spleen, liver and brain of Pb-intoxicated animals. Our data demonstrated that the intoxication of ICR male mice with Pb salt resulted in a significant accumulation of Pb in all studied organs of the mice compared to the untreated control animals. The biodistribution of the toxic metal was in the order kidneys>spleen>liver>brain. The treatment of the Pb-intoxicated animals with tetraethylammonium salts of monensic and salinomycinic acids significantly decreased the concentration of the toxic metal ion compared to the toxic control. The effect varied in the interval 38% (for kidneys) to 52% (for brain) compared to the toxic control group (Pb). The tetraethylammonium salt of salinomycinic acid was more effective in reducing the Pb concentration in the brain of the Pb-treated mice compared to monensin. Pb-intoxication did not affect significantly the Zn endogenous concentration compared to the normal values. The treatment of ICR male mice with Pb-salt decreased the Cu concentration in the spleen and increased the Cu concentration in the liver compared to the untreated control animals. The detoxification of the Pb-intoxicated mice with tetraethylammonium salts of salinomycinic and monensic acids restored the Cu concentration in the spleen, but did not affect the Cu levels in the liver. The Pb-intoxication of the ICR mice resulted in a significant decrease of the Fe-concentration in the spleen and liver compared to the untreated control animals. The administration of the tetraethylammonium salts of salinomycinic and monensic acids to the Pb-treated animals restored the levels of Fe in both organs.

Sterically stabilized liposomes as a platform for salinomycin metal coordination compounds: physicochemical characterization and in vitro evaluation

Sterically stabilized DPPC:CHOL:DSPE-PEG-2000 liposomal formulations of the lipophilic complexes of salinomycin with Na(I), K(I), Mn(II), Co(II), and Ni(II) ions were prepared by film-hydration method at different drug-to-DPPC molar ratios. For the K(I) and Na(I) complexes, optimal loading was established at a drug-to-DPPC molar ratio of 0.5:1, whereas for the Me(II) complexes, it was encountered at 0.1:1. DLS revealed uniform LUV populations (130–160 nm) with monomodal size distribution, further corroborated by AFM. Free and entrapped salinomycinates exhibited cytotoxicity in three human tumor cell lines, whereby the liposomal agents were superior vs. free complexes. DNA-fragmentation and flow cytometric assays showed that the cytotoxicity of free and liposomal salinomycinates is mediated by the induction of apoptosis and G 1 arrest. The ability of the carriers to retain the bio-activity of the entrapped cargo gives us reason to conclude that the presented DPPC:CHOL:DSPE- PEG-2000 liposomes are suitable platforms for the salinomycin complexes, needing further evaluation and optimization.

Effects of cadmium and monensin on renal and cardiac functions of mice subjected to subacute cadmium intoxication.

ABSTRACT Cadmium (Cd) is a well-known nephrotoxic agent. Cd-induced renal dysfunction has been considered as one of the causes leading to the development of hypertension. The correlation between Cd concentration in blood and urine and cardiovascular diseases has been discussed in many epidemiological studies. A therapy with chelating agents is utilized for the treatment of toxic metal intoxication. Herein we present novel information indicating that monensin (applied as tetraethylammonium salt) is a promising chelating agent for the treatment of Cd-induced renal and cardiac dysfunction. The study was performed using the ICR mouse model. Adult ICR male mice were divided into three groups with six animals in each group: control (received distilled water and food ad libitum for 28 days); Cd-intoxicated (treated orally with 20 mg/kg b.w. Cd(II) acetate from day 1 to day 14 of the experimental protocol), and monensin treated group (intoxicated with Cd(II) acetate as described for the Cd-intoxicated group followed by oral treatment with 16 mg/kg b.w. tetraethylammonium salt of monensic acid for 2 weeks). Cd intoxication of the animals resulted in an increase of the organ weight/body weight indexes. Cd elevated significantly creatinine and glucose level in serum. Monensin treatment improved the organ weight/body weight ratios. The therapy of the Cd-intoxicated animals with monensin ameliorated the creatinine and glucose level in serum and decreased the concentration of the toxic metal ions in the heart and kidneys by 54 % and 64 %, respectively