Activity

Seriniquinone is a secondary metabolite isolated from a rare marine bacterium of the genus Serinicoccus. This natural quinone is highlighted for its selective cytotoxic activity toward melanoma cancer cells, in which rapid metastatic properties are still a challenge for clinical treatment of malignant melanoma. The progress of seriniquinone as a promising bioactive molecule for drug development requires the assessment of its clinical interaction potential with other drugs. This study aimed to investigate the in vitro inhibitory effects of seriniquinone on the main human CYP450 isoforms involved in drug metabolism. The results showed strong inhibition of CYP1A2, CYP2E1 and CYP3A, with IC50 values up to 1.4 μM, and moderate inhibition of CYP2C19, with IC50 value >15 μM. Detailed experiments performed with human liver microsomes showed that the inhibition of CYP450 isoforms can be explained by competitive and non-competitive inhibition mechanisms. In addition, seriniquinone demonstrated to be an irreversible and time-dependent inhibitor of CYP1A2 and CYP3A. The low inhibition constants values obtained experimentally suggest that concomitant intake of seriniquinone with drug metabolized by these isoforms should be carefully monitored for adverse effects or therapeutic failure. This study aimed to investigate the toxic effects of microcystin-LR (MC-LR), which is released from several bloom-forming cyanobacteria, on the glucose metabolism of pancreatic β cells in vivo and in vitro. Male mice and the pancreatic MIN6 cells were respectively treated with varying concentrations of MC-LR. After 3- or 6- months of MC-LR exposure, increase in the body weight of mice was found to be inhibited, and the structure of their pancreatic tissues was damaged with impaired glucose tolerance and impaired insulin secretion. Further, these toxic effects became more pronounced with time and with increased dosages. Direct cytotoxic effects of MC-LR were observed in the MIN6 pancreatic β-cells possibly due to their expression of the MC-LR specific transporter. MC-LR entered the MIN6 cells that significantly reduced the cell viability. Both in vivo and in vitro experiments demonstrated that MC-LR was able to induce apoptosis, possibly associated with mitochondrial damage. Above all, these findings implied that MC-LR may be transported into the pancreatic β cells and cause subsequent cytotoxicity. V.Arsenic (As) is a toxic element that is highly abundant in the environment. However, there has not been sufficient research into the mechanisms of arsenic-induced transgenerational effects. In biomedical and environmental toxicology research field, C. elegans are often used as the ideal model. In this study, F0 generation animals were cultured with arsenite, while subsequent generations animals (F1 – F6) were cultured in the absence of arsenic. Experiments were performed to examine the transgenerational glycometabolism and the associated mechanisms in all seven generations (F0 – F6) of C. elegans. Results show that arsenite exposure increased total glucose content but reduced glucose metabolites in F0 generation C. elegans. The total glucose content was also elevated in subsequent generations probably due to transgenerational downregulation of fgt-1. In addition, arsenite exposure induced transgenerational downregulation of histone demethyltransferase spr-5 and elevated histone dimethylation in F0 generation. This study highlights that single generation exposure to arsenite causes transgenerational changes in glycometabolism in C. elegans, which may be caused by downregulation of spr-5 and elevation of H3K4me2. Our previous study demonstrated that cadmium (Cd) is an effective inducer of mitophagy, which is mainly mediated by PINK1/Parkin pathway. However, the role of other mitophagy pathways in Cd-induced mitophagy remains elusive. The present study employed HeLa cells, lacking fully functional Parkin, as a cell model to study Parkin-independent mitophagy pathway induced by Cd. Our results showed that BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (Bnip3L/NIX), an outer mitochondrial membrane mitophagy receptor, could provide an alternate pathway for Cd-induced mitophagy in HeLa cells. Specifically, 10 μM Cd for 12 h induced mitophagy in GM00637 and HeLa cells which was assessed by mitochondrial fusion to lysosomes and decreased expression of mitochondrial markers such as COX-IV and HSP60. Notably, in GM00637 cells, Cd-induced mitophagy was predominantly mediated by PINK1/Parkin pathway as evinced by translocation of Parkin to mitochondria. Interestingly, in HeLa cells, significant increase in NIX expression was occurred and mitophagy was induced under Cd exposure, suggesting NIX compensates lost role of Parkin in Cd-induced mitophagy in HeLa cells. These results were verified by knocking down NIX using siRNA in HeLa cells, which lead to abolished mitophagy process. Moreover, NIX phosphorylation at serine-81 significantly increased in cells treated with Cd implying that phosphorylation of NIX plays an important role in NIX-mediated mitophagy. These findings reveal a novel mechanism of Cd toxicity and suggest a compensatory role of NIX in Cd-induced mitophagy. Tacrolimus Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p less then 0.