Yordanka Gluhcheva

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.

Interferon-γ-mediated pathways are induced in human CD34+ haematopoietic stem cells

Pro-inflammatory cytokines like interferon-gamma (IFN-gamma) are considered to be important in the development of anaemia of chronic disease (ACD). Both, inhibitory and stimulatory activities of IFN-gamma on erythropoiesis have been observed in vitro earlier. IFN-gamma induces several biochemical pathways in human monocytes, among them neopterin formation by GTP-cyclohydrolase I (GTP-CH I) and tryptophan degradation by the enzyme indoleamine 2,3-dioxygenase (IDO). IDO-mediated tryptophan deprivation efficiently inhibits the growth of proliferating cells and microbes, thus we wanted to examine whether enhanced tryptophan degradation by monocytic precursor cells also suppresses erythropoiesis. Therefore, IFN-gamma-mediated pathways were investigated in human CD34(+) progenitor cells, and effects of IFN-gamma on the proliferative activity of different progenitor subpopulations were studied. Cells were either cultivated in agar-conditioned medium (ACM) or in medium containing erythroid growth factors interleukin-3 (IL-3) and stem cell factor (SCF; EGFCM). Stimulation of CD34(+) cells with IFN-gamma in different doses (either 5000U/ml once or 200 and 400U/ml every other day) induced tryptophan degradation and in parallel also neopterin formation. Unstimulated cells cultured with ACM produced higher amounts of neopterin and kynurenine (all p<0.05). IFN-gamma stimulated higher kynurenine and neopterin formation in cells cultivated in EGFCM, stimulation with 400U IFN-gamma every other day was most effective. IFN-gamma stimulated the growth and proliferation of CFU-E and BFU-E (3-8) in both media. In conclusion, stimulation of haematopoietic stem cells with IFN-gamma activates IDO and neopterin formation, and it also exerts an influence on the proliferation of various stem cell populations.

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.

Platelet morphological, functional and rheological properties attributable to addictions.

Hemorheological abnormalities such as elevated whole blood viscosity, plasma viscosity, erythrocyte deformability and platelet aggregation, hematocrit and fibrinogen levels, are frequently examined as diagnostic tool and prognostic relevance in socially important hemorheological disorders. Distinct biological - morphological and functional platelet alterations, have been described in different addictions (heroin-, cocaine-, nicotine-, alcohol-, etc.). Chronic addictions could cause biochemical and conformational changes in platelets and their membranes, thus modulating platelet receptor expression, morphology (anisocytosis, giant platelets) and activation (alpha-granule release), platelet aggregation and hemorheological properties. Some of these alterations in chronic addicts - documented at cellular- and molecular level, could be easily used as a precise diagnostic tool with regard to thromboembolic complications and microcirulation injuries attributable to addictions. The present review focuses on some changes in platelet morphological, functional and rheological properties induced by chronic opiate/opioid abuse. Hypothesis is accumulated that free fatty acids (FFAs) and especially oleic acid (OA) could cause positive molecular and conformational changes in platelets of addicts with hemorheological disorders.

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.

Cobalt(II)-Induced Changes in Hemoglobin Content and Iron Concentration in Mice from Different Age Groups

ABSTRACT Cobalt (Co) and its compounds are shown to improve hematological parameters. Long-term treatment with Co(II) increased hemoglobin content in a dose- and time-dependent manner in mature mice (day 45 to day 90) while it was reduced in immature mice (day 18 to day 30). Higher Hb was measured in samples treated with CoCl2 compared to those treated with Co-EDTA. Plasma Fe concentration was significantly higher in samples treated with Co-EDTA compared to those exposed to CoCl2. Lower concentrations were measured only in mature animals. Co(II) concentration increased but not in a dose-dependent manner. In general more Co(II) was measured in samples treated with CoCl2 possibly due to the stability of the complex Co-EDTA. Surprisingly, mature mice had less Co(II) in their plasma compared to day 18 mice. Strong correlation between plasma Co(II) and iron concentration was found in samples of mice treated with Co-EDTA. Co(II) concentration showed inverse correlation with hemoglobin in mice treated with low dose Co-EDTA. Such relationship was found for day 45 and day 60 mice exposed to high dose CoCl2. Immature mice are more sensitive to Co(II) treatment and show signs of anemia. It has a significant impact on hemoglobin biosynthesis possibly due to its effect on iron metabolism.

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.

Hematological changes in case of chronic cadmium intoxication and monensin detoxication. Relationship with rheological variables

The study evaluated the affect of chronic cadmium (Cd) and monensin treatment on some hematological parameters and its relationship with the rheological variables. Adult male mice were subjected to chronic treatment with cadmium acetate [Cd(CH3COO)2 × 2H2O] (group 1), Cd(CH3COO)2 × 2H2O followed by treatment with low dose monensin (group 2) and Cd(CH3COO)2 × 2H2O followed by high dose monensin treatment (group 3). Cd(CH3COO)2 × 2H2O and deprotonated monensin were dissolved in distilled water and given daily to the experimental animals. Mice drinking distilled water served as a control group (group 4). Hematological parameters and erythrocyte morphology were evaluated in parallel with whole blood viscosity (WBV). Cd treatment reduced Hb and increased RDW. The addition of high dose monensin significantly improved erythrocytic indices compared to the control. Erythrocyte anisocytosis was observed in blood smears of Cd-treated mice corresponding to the increased RDW. WBV was significantly elevated in the experimental groups in the whole range of shear rates compared to the control group and in groups 2 and 3 was lower than in group 1 but remained higher compared to group 4. Correlations were found between WBV and RBC, Hb, Hct, MCV and RDW. The results suggest that hemorheological parameters such as WBV should be monitored in parallel with the hematological parameters when monensin is applied and heavy metal intoxication is suspected.

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

Monensin ameliorates cadmium-induced hepatic injury in mice, subjected to subacute cadmium intoxication

This study was designed to evaluate the potential application of monensin as an oral drug for the treatment of cadmium-induced hepatic dysfunction. The study was performed using ICR mouse model. Twenty-seven adult ICR male mice were divided into three groups of nine animals each: 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 the 1st to the 14th day of the experimental protocol); and monensin treated group (intoxicated with Cd(II) acetate as described for the Cd-intoxicated group followed by an oral treatment with 16 mg/kg b.w. tetraethylammonium salt of monensic acid for two weeks). The obtained results demonstrated that the treatment of Cd-intoxicated animals with monensin restored the liver weight/body weight index to normal values, decreased the concentration of the toxic metal ion by 50% compared to the Cd-treated controls, and recovered the homeostasis of Cu and Zn. Monensin reduced the activity of aspartate aminotransferase, alanine aminotrasnferase and alkaline phosphatase in the plasma of Cd-treated animals to the normal control levels and ameliorated the Cd-induced inflammation in the liver. Taken together, these data demonstrated that monensin could be an effective chelating agent for the treatment of Cd-induced hepatotoxicity.