Trace elements dyshomeostasis in liver and brain of weanling mice under altered dietary selenium conditions.

BACKGROUND: A balanced diet containing selenium (Se) and other trace elements is essential for normal development and growth. Se has been recognized as an essential trace element; however, its interaction with other elements has not been fully investigated. In the present study, sodium (Na), magnesium (Mg), potassium (K), calcium (Ca), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), Se and rubidium (Rb), were analysed in liver and brain regions under altered dietary Se intake in weanling mice to identify major discriminatory elements. METHODS: The study investigated the effects of different levels of Se intake on the elemental composition in liver and brain tissues of weaned mice. After 24 weeks of feeding with Se adequate, deficient, and excess diets, elemental analysis was performed on the harvested tissues using Inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis that included analysis of covariance (ANCOVA), correlation coefficient analysis, principal component analysis, and partial least squares discriminant analysis were performed. RESULTS: The ANCOVA showed statistically significant changes and correlations among the analysed elements under altered dietary Se status. The multivariate analysis showed differential changes in elements in liver and brain regions. The results suggest that long-term dietary Se alternations lead to dyshomeostasis in trace elements that are required in higher concentrations compared to Se. It was observed that changes in the Fe, Co, and Rb levels were similar in all the tissues studied, whereas the changes in Mg, Cr, and Mn levels were different among the tissues under altered dietary Se status. Additionally, the changes in Rb levels correlated with the dietary Se intake but had no relation with the tissue Se levels. CONCLUSIONS: The findings suggest interactions between Mg, Cr, Mn, Fe, Co, and Se under altered Se status may impact cellular functions during postnatal development. However, the possible biological significance of alterations in Rb levels under different dietary Se paradigms needs to be further explored.

Quantum mechanical treatment of As3+-thiol model compounds: implication for the core structure of As(III)-metallothionein.

Exposure to inorganic arsenic (As) is one of the major health concerns in several regions around the world. Binding of As(III) with thiols is central to the mechanisms related to its toxicity, detoxification, and therapeutic effects. Due to its high thiol content, metallothionein (MT) is presumed to play an important role in case of arsenic toxicity. Consequences of these As-thiol interactions are not yet clear due to various difficulties in the characterization of arsenic bound proteins by spectroscopic techniques. Computational modeling can be a reliable approach in predicting the molecular structures of such complexes. This paper presents the results of a systematic study on different As(III)-thiol model compounds conducted by both ab initio and DFT methods with different Gaussian type basis sets. Proficiency of these theoretical methods has been evaluated in terms of bond lengths, bond angles, free energy, partial atomic charges, computational cost, and comparison with the experimental data. It has been demonstrated that the DFT-B3LYP/6-311+G(3df) functional offers better accuracy in predicting the structure and the UV absorption spectra of As(III)-thiol complexes. The results of the present study also helps in defining the boundaries for the core of arsenic bound MT so that quantum mechanical/molecular mechanical (QM/MM) methods can be employed to predict the structural and functional aspects of the protein. Graphical Abstract Optimized structural parameters of As3+-thiol model compounds.

Pro-Oxidant Role of Silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR Metabolomic and Biochemical Study.

Silibinin, a major bioactive flavonolignan in Silybum marianum, has received considerable attention in view of its anticarcinogenic activity. The present study examines its anticancer potential against 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin cancer. Male LACA mice were randomly segregated into 4 groups: Control, DMBA/TPA, Silibinin and Silibinin+DMBA/TPA. Tumors in DMBA/TPA and Silibinin+DMBA/TPA groups were histologically graded as squamous cell carcinoma. In the Silibinin+DMBA/TPA group, significant reduction in tumor incidence (23%), tumor volume (64.4%), and tumor burden (84.8%) was observed when compared to the DMBA/TPA group. The underlying protective mechanism of Silibinin action was studied at pre-initiation (2 weeks), post-initiation (10 weeks) and promotion (22 weeks) stages of the skin carcinogenesis. The antioxidant nature of Silibinin was evident at the end of 2 weeks of its treatment. However, towards the end of 10 and 22 weeks, elevated lipid peroxidation (LPO) levels indicate the pro-oxidative nature of Silibinin in the cancerous tissue. TUNEL assay revealed enhanced apoptosis in the Silibinin+DMBA/TPA group with respect to the DMBA/TPA group. Therefore, it may be suggested that raised LPO could be responsible for triggering apoptosis in the Silibinin+DMBA/TPA group. 1H Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the metabolic profile of the skin /skin tumors. Dimethylamine (DMA), glycerophosphocholine (GPC), glucose, lactic acid, taurine and guanine were identified as the major contributors for separation between the groups from the Principal Component Analysis (PCA) of the metabolite data. Enhanced DMA levels with no alteration in GPC, glucose and lactate levels reflect altered choline metabolism with no marked Warburg effect in skin tumors. However, elevated guanine levels with potent suppression of taurine and glucose levels in the Silibinin+DMBA/TPA group are suggestive of the pro-oxidative nature of Silibinin in regressing tumors. Thus, supporting the theory of augmented LPO levels resulting in increased apoptosis in the skin tumors treated with Silibinin.

Protective Effects of Zinc Against Acute Arsenic Toxicity by Regulating Antioxidant Defense System and Cumulative Metallothionein Expression.

Arsenic (As), a toxic metalloid, is one of the major global concerns. The toxicity resulting from As exposure is linked to the generation of reactive oxygen intermediates during their redox cycling and metabolic activation processes that cause lipid peroxidation (LPO). Zinc (Zn), a redox-inactive metal, helps to maintain cellular functions because of its prominent role in antioxidant network through multiple mechanisms. The present study, therefore, explores the effectiveness of administered Zn to combat against acute As toxicity by analysis of antioxidant defense status, alkaline phosphatase (ALP) activity, histological profile, MT expression, and elemental status in rat liver. To achieve this goal, four experimental groups, one control and three receiving different metal supplementations, were chosen (group 1, control; group 2, Zn supplemented; group 3, As substituted; group 4, Zn + As supplemented). The levels of reduced glutathione (GSH) and activities of glutathione reductase (GR) and ALP were lowered, whereas LPO levels and activity of superoxide dismutase (SOD) were elevated with no significant change in catalase (CAT) activity. Histopathological changes were also observed in the As substituted group in comparison to the control. Particle-induced X-ray emission (PIXE) analysis showed decrease in Fe and S concentration in rat liver after As intoxication, whereas As was below detection limit, i.e., <1 ppm. Zn administration almost restored the antioxidants, ALP activity, histopathological changes, and elemental status. A cumulative increase in MT expression was found with the combined treatment of Zn and As. Also, Zn alone caused no significant change in the antioxidant defense system. It can be concluded that restoration of antioxidant activity and increased MT expression are the two independent protective mechanisms of Zn to reduce acute As toxicity.