Evaluation of sesamol-induced histopathological, biochemical, haematological and genomic alteration after acute oral toxicity in female C57BL/6 mice

The objective of this study was to evaluate organ-wise toxicological effects of sesamol and determine the LD50 cut-off value and GHS category following acute oral toxicity method OECD 423. An acute oral toxicity study was carried out in female C57BL/6 mice. Observations for physical behaviour and measurements on haematology, biochemistry, histology of vital organs were performed. In addition, genotoxicity assessment using comet and micronuclei assays was also performed. Acute toxicological effects were observed at 2000 mg/kg, while no adverse effects observed at 300 mg/kg. The effects of 2000 mg/kg were manifested as severe histopathological changes in all organs (femur, spleen, gastrointestine, lungs, heart, kidney, liver, stomach and brain) and excessive DNA strands breaks occurred in femoral bone marrow cells and splenocytes. A single dose of sesamol (2000 mg/kg, body weight) caused the death of two mice (out of three) within 2 h. Hence, sesamol is in GHS category 4 (>300–2000) with LD50 cut-off value of 500 mg/kg body weight. In contrast, this study is correlated with the obtained GHS category 4 and LD50 cut-off value 580 mg/kg body weight by ProTox. In conclusions, the present study has classified sesamol toxicity and assessed organ-wise acute oral toxicity of sesamol in female C57BL/6 mice. Therefore, these findings may be useful for the selection of dosages for further pre-clinical evaluation and potential drug developmental of sesamol. Keywords: Sesamol, Acute toxicity, Comet assay, Micronucleus assay, Histopathology, Haematolog

Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM

Investigations on the role of intracellular Ca(2+) ion concentration in the mechanism of development of COPD in smokers and non-smokers were carried out. The intracellular Ca(2+) levels were found to be increased in human lymphocytes in patients with COPD as compared to non-smokers and smokers without COPD. The investigations reveal an association in altered intracellular Ca(2+) regulation in lymphocytes and severity of COPD, by means of significant activation of Protein kinase C and inducible nitric oxide synthase (iNOS). The effect of a novel calcium channel blocker ethyl 4-(4'-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM) as a potential candidate for the treatment of COPD was also investigated. H-DHPM treated cells showed a decrease in intracellular Ca(2+) level as compared to the control cells. Molecular studies were carried out to evaluate the expression profile of NOS isoforms in human lymphocytes and it was shown that H-DHPM decreases the increased iNOS in COPD along with reestablishing the normal levels of endothelial nitric oxide synthase (eNOS). The results of H-DHPM were comparable with those of Amlodipine, a known calcium channel blocker. Calcium channel blocker H-DHPM proves to be a potential candidate for the treatment of COPD and further clinical studies are required to prove its role in the treatment of pulmonary hypertension (PH). (C) 2011 Elsevier Masson SAS. All rights reserved