The Mitochondria-Targeted Antioxidants and Remote Kidney Preconditioning Ameliorate Brain Damage through Kidney-to-Brain Cross-Talk

Background

Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies.

Methodology/Principal Findings

We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced phosphorylation of GSK-3β in neuronal cells.

Conclusion

The results indicate that renal preconditioning and SkQR1-induced brain protection may be mediated through the release of EPO from the kidney.     

Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine

Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown. Here, we present a set of high-resolution X-ray crystal structures that explain why CHL is unable to inhibit peptide bond formation between the incoming glycyl-tRNA and a nascent peptide that otherwise is conducive to the drug action. Our structures reveal that fully accommodated glycine residue can co-exist in the A site with the ribosome-bound CHL. Moreover, binding of CHL to a ribosome complex carrying glycyl-tRNA does not affect the positions of the reacting substrates, leaving the peptide bond formation reaction unperturbed. These data exemplify how small-molecule inhibitors can reshape the A-site amino acid binding pocket rendering it permissive only for specific amino acid residues and rejective for the other substrates extending our detailed understanding of the modes of action of ribosomal antibiotics.     

Intra-annual variation of phytoplankton community responses to factorial N,P, and CO2 enrichment in a temperate mesotrophic lake

1. Across primary producer communities in different lakes, nitrogen (N) and phosphorus (P) can exhibit many different patterns of limitation. Here, we look at the intra-annual variability of these patterns in a single lake. Furthermore, we investigate whether a third resource, carbon dioxide (CO₂) can have significant effects on phytoplankton biomass and community composition.
2. We performed five in situ lacustrine mesocosm experiments at different times of the year. In each experiment, we had a factorial design with two levels of N, P and CO₂ enrichment (no enrichment or double lake concentrations for N and P and atmospheric (400 ppm) and c. 1,000 ppm for CO₂) resulting in a total of eight treatments. Mesocosms of c. 1,600 L were suspended in a temperate, mesotrophic lake (Lac Hertel, Canada). Each experiment lasted 2 weeks and chlorophyll a biomass, coarse chemotaxonomic community composition (measured using fluorometry), and several environmental variables were recorded at a minimum of four time points.
3. We found that the limiting, synergistic, and community composition effects of N and P varied between experiments. TN:TP ratios explained, in part, some of this variability, along with insolation and water temperature.
4. Despite relatively high levels of CO₂ in the control mesocosms, we found a constant synergistic effect of CO₂ with N. In combination with the synergistic effect of P with N found in some experiments, this provides support for CO₂ as one of the multiple limiting resources in nutrient-enriched systems. This finding could have implications for eutrophic lakes exposed to increasing concentrations of CO₂.
5. We also found that the effects of CO₂ on community composition varied intra-annually. Thus, we conclude that generalised predictions about the effect of CO₂ on community composition at a coarse chemotaxonomic scale are unlikely to hold, but predictions specific to season and system are likely to be reliable.