Sexual dimorphism modulates metabolic and cognitive alterations under HFD nutrition and chronic stress exposure in mice. Correlation between spatial memory impairment and BDNF mRNA expression in hippocampus and spleen.

AIMS: The accumulated evidence suggests that lifestyle - specifically dietary habits and stress exposure - plays a detrimental role in health. The purpose of the present study was to analyze the interplay of stress, diet, and sex in metabolic and cognitive alterations. MAIN METHODS: For this purpose, one-month-old C57Bl/6J mice were fed with a standard diet or high-fat diet (HFD). After eight weeks, one subgroup of mice from each respective diet was exposed to 20 weeks of chronic mild stress (CMS), whilst the others were left undisturbed. KEY FINDINGS: After 28 weeks of HFD feeding, mice from both sexes were overweight, with an increase in caloric intake and abdominal and subcutaneous fat pads. Stress exposure induced a decrease in body weight, related to a decrease in caloric efficiency in both males and females. Results indicate that males are more susceptible than the females in modulating metabolic and cognitive functions under HFD and CMS. Although both sexes demonstrated HFD-induced weight gain, fat accumulation, insulin resistance, high cholesterol, only males exposed to CMS but not females have (i) impaired glucose tolerance with higher glucose level; (ii) significant prolonged latency in Barnes test, suggesting cognitive impairment; (iii) increased IFN-gamma expression in hippocampus, suggesting greater neuroinflammatory response; (iv) poorer cognitive performance related to a decrease in hippocampal and spleen BDNF mRNA expression. SIGNIFICANCE: The main finding in this study is the presence of a sexual dimorphism in modulating metabolic and cognitive functions under HFD and CMS, showing males are more susceptible than females. In addition, poorer cognitive performance was related to a decrease in hippocampal BDNF mRNA expression. Interestingly, these changes were observed in the spleen as well.

Doramectin induced cytotoxic and genotoxic effects on bovine peripheral lymphocytes and cumulus cells in vitro.

The effect of doramectin (DOR) was tested on two experimental somatic bovine cells in vitro: peripheral lymphocytes (PL) and cumulus cells (CC). The cytotoxicity and genotoxicity of DOR were assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, single cell gel electrophoresis assay (SCGE) and cytokinesis-block micronucleus cytome (CBMN Cyt) assay. Both cells were treated with three concentrations of DOR (20, 40, 60 ng mL-1) for 24 h. The results obtained from PL demonstrated that DOR was able to induce cytotoxic effect and DNA damage with all concentrations tested. Additionally, DOR increased micronuclei (MNi) frequency and nuclear buds (NBuds) with 20, 40, 60 ng mL-1, and nucleoplasmic bridges (NPBs) only with 40 ng mL-1. On the other hand, the three concentrations of DOR were not able to induce cytotoxic effect and DNA damage using SCGE in the bovine CC. Nevertheless, the two higher concentrations of DOR (20, 40 µg mL-1) significantly increased the frequency of micronucleus formation in bovine CC. These results represent the first experimental evidence of genotoxic and cytotoxic effects exerted by DOR on bovine PL and CC.

Assessment of bendamustine-induced genotoxicity in eukaryotic cells.

Bendamustine, an anticancer drug with alkylating properties, is widely used to treat hematological malignancies. Since the nitrogen mustard family alkylators induce DNA damages and have been associated with an elevated risk of second malignancy, current study evaluates the cytotoxic, mutagenic, and recombinogenic effects of bendamustine by using, respectively the mitotic index assay, the in vitro mammalian cell micronucleus test (Mnvit) and the chromosome aberration (CA) test in human peripheral lymphocytes, and the in vivo homozygotization assay in Aspergillus nidulans, which detects the loss of heterozygosity (LOH) due to somatic recombination. Bendamustine (6.0 µg/ml, 9.0 µg/ml, and 12.0 µg/ml) induced a statistically significant concentration-related increase in the frequencies of micronuclei and a significant reduction in the cytokinesis block proliferation index (CBPI) rates when compared to negative control. In the CA test, bendamustine significantly increased the frequencies of structural aberrations at the three tested concentrations when compared to the negative control. Aspergillus nidulans diploids, obtained after bendamustine treatment (6.0 µg/ml, 12.0 µg/ml, and 24.0 µg/ml), produced, after haploidization, homozygotization index (HI) rates higher than 2.0 and significantly different from the negative control. Since bendamustine showed genotoxic effects in all tested concentrations, two of them corresponding to the peak plasma concentrations observed in cancer patients treated with bendamustine, data provided in the current research work may be useful to identify the most appropriate dosage regimen to achieve the efficacy and safety of this anticancer medication.