Effects of waterborne cadmium exposure on Spinibarbus sinensis hepatopancreas and kidney: Mitochondrial cadmium accumulation and respiratory metabolism.

To examine the relationship between heavy metal accumulation in mitochondria and their respiration function in fish during in vivo exposure, juvenile Spinibarbus sinensis were exposed to different waterborne cadmium (Cd) concentrations for up to 28 days. We measured the state III respiration rate and cytochrome c oxidase (CCO) activity of mitochondria in hepatopancreas and kidney and the accumulated Cd concentrations in mitochondria and heat-stable protein (HSP) fractions. Dose- and time-dependent Cd accumulation occurred at different levels in both organs, but was lower in hepatopancreas. When hepatopancreas mitochondrial Cd concentrations in Cd-exposed groups were > 5.5 µg/g dwt, their state III respiration rates were significantly lower than the control. CCO activity of hepatopancreas mitochondria exhibited decreasing dose- and time-dependent trends. However, kidney mitochondria respiratory activities were not affected significantly by Cd exposure. Cd concentrations in kidney HSP fraction were 2-5 times higher than in hepatopancreas under all exposure conditions, and were mainly present as non-deleterious metallothionein (MT)-Cd complexes. These results suggest that Cd accumulation occurred in hepatopancreas and kidney mitochondria of S. sinensis following waterborne Cd exposure, which significantly inhibited the respiration function of hepatopancreas mitochondria but did not have a deleterious effect on kidney mitochondria. The inhibitory pattern of hepatopancreas mitochondrial Cd concentrations related to function exhibited threshold and saturation effects, suggesting the capacity of S. sinensis to manage Cd toxicity. The difference in the relative proportion of Cd occurring as MT-Cd complexes in organs likely causes the organ-specific effects of Cd on hepatopancreas and kidney mitochondrial function.

Tissue-Specific Antioxidative Responses and Cadmium Accumulation in Silurus meridionalis Under Chronic Waterborne Cadmium Exposure.

In this study, the oxidative damage, antioxidative responses and cadmium (Cd) accumulation in juvenile Silurus meridionalis were studied, after S. meridionalis were exposed to 0 (control), 62.5, 125, 250 and 500 µg Cd/L for 56 days. Cd accumulation, malondialdehyde, superoxide dismutase (SOD), catalase, glutathione (GSH) and total antioxidant capacity (T-AOC) were determined in gill, liver, kidney and intestine tissues. The results showed that the Cd accumulation in S. meridionalis was dose-dependent and tissue-specific, with the highest Cd content in the kidney, followed by the liver, gill, and intestine. Waterborne Cd stress in S. meridionalis was expressed as tissue-specific oxidative damage and antioxidant responses in gill, liver, kidney and intestine tissues. Waterborne Cd exposure induced the most significant oxidative damage in the gill, followed by the liver and kidney, while the intestine showed no sensitivity to waterborne Cd exposure. The antioxidants, such as SOD in the liver, kidney and intestine, as well as T-AOC and GSH in the gill, liver and kidney, were sensitive to waterborne Cd exposure.

Combined 3D-QSAR, molecular docking, and molecular dynamics study on piperazinyl-glutamate-pyridines/pyrimidines as potent P2Y12 antagonists for inhibition of platelet aggregation.

An unusually large data set of 397 piperazinyl-glutamate-pyridines/pyrimidines as potent orally bioavailable P2Y(12) antagonists for inhibition of platelet aggregation was studied for the first time based on the combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) methods. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies have been performed with a training set of 317 compounds, estimating three superimposition methods. The best CoMFA and CoMSIA models, derived from superimposition I, shows leave-one-out cross-validation correlation coefficients (Q(2)) of 0.571 and 0.592 as well as the conventional correlation coefficients (R(2)(ncv)) of 0.814 and 0.834, respectively. In addition, the satisfactory results, based on the bootstrapping analysis and 10-fold cross-validation, further indicate the highly statistical significance of the optimal models. The external predictive abilities of these models were evaluated using a prediction set of 80 compounds, producing the predicted correlation coefficients (R(2)(pred)) of 0.664 and 0.668, respectively. The key amino acid residues were identified by molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good concordance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the rational modification of molecules in order to design more potent P2Y(12) antagonists. We hope the developed models could provide some instructions for further synthesis of highly potent P2Y(12) antagonists.