Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients.

Exercise tolerance is impaired in hypoxia, and it has recently been shown that dietary nitrate supplementation can reduce the oxygen (O(2)) cost of muscle contractions. Therefore, we investigated the effect of dietary nitrate supplementation on arterial, muscle, and cerebral oxygenation status, symptoms of acute mountain sickness (AMS), and exercise tolerance at simulated 5,000 m altitude. Fifteen young, healthy volunteers participated in three experimental sessions according to a crossover study design. From 6 days prior to each session, subjects received either beetroot (BR) juice delivering 0.07 mmol nitrate/kg body wt/day or a control drink (CON). One session was in normoxia with CON (NOR(CON)); the two other sessions were in hypoxia (11% O(2)), with either CON (HYP(CON)) or BR (HYP(BR)). Subjects first cycled for 20 min at 45% of peak O(2) consumption (VO(2)peak; EX(45%)) and thereafter, performed a maximal incremental exercise test (EX(max)). Whole-body VO(2), arterial O(2) saturation (%SpO(2)) via pulsoximetry, and tissue oxygenation index of both muscle (TOI(M)) and cerebral (TOI(C)) tissue by near-infrared spectroscopy were measured. Hypoxia per se substantially reduced VO(2)peak, %SpO(2), TOI(M), and TOI(C) (NOR(CON) vs. HYP(CON), P < 0.05). Compared with HYP(CON), VO(2) at rest and during EX(45%) was lower in HYP(BR) (P < 0.05), whereas %SpO(2) was higher (P < 0.05). TOI(M) was ~4-5% higher in HYP(BR) than in HYP(CON) both at rest and during EX(45%) and EX(max) (P < 0.05). TOI(C) as well as the incidence of AMS symptoms were similar between HYP(CON) and HYP(BR) at any time. Hypoxia reduced time to exhaustion in EX(max) by 36% (P < 0.05), but this ergolytic effect was partly negated by BR (+5%, P < 0.05). Short-term dietary nitrate supplementation improves arterial and muscle oxygenation status but not cerebral oxygenation status during exercise in severe hypoxia. This is associated with improved exercise tolerance against the background of a similar incidence of AMS.

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

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Electrospray coupled with tandem mass spectrometry is shown to have utility in determining the molecular mass and the sequence of short modified oligonucleotides. The product ion spectrum of a triply deprotonated molecule precursor is dominated by ions formed via two fragmentation pathways: first, fragmentation across the SP-0 phosphate bond, and second, loss of a non-terminal base with concomitant cleavage of the ribose 3'C-O bond. If either of these two pathways is complete with fragmentation occurring at each equivalent position along the phosphadiester backbone, then the oligomer may be sequenced. Alternatively, if both these pathways are only partially complete, their complementarity may be used for more extensive sequencing. The inductive effect of the modification on the nucleobase is shown to influence the latter fragmentation process. The greater the electron affinity of the base modification, the more facile is the loss of that base when the molecule is collisionally activated. In fact, this latter fragmentation dominates the product ion spectrum when a nucleobase contains a substituent that is highly inductively withdrawing. This domination can be such that few other first-generation fragment ions are present in the product ion spectrum. Sequence information may then require utilization of second-generation product ions.

We have selected aptamers binding to lysozyme from a DNA library using capillary electrophoresis-systematic evolution of ligands by exponential enrichment. During the selection process the dissociation constant of the ssDNA pool decreased from the micromolar to the low nanomolar range within five rounds of selection. The final aptamer had a dissociation constant of 2.8 ± 0.3 nM, 6.1 ± 0.5 nM, and 52.9 ± 9.1 nM as determined by fluorescence anisotropy, surface plasmon resonance and affinity capillary electrophoresis respectively. The aptamers were successfully challenged for specificity against other egg white proteins. The high affinity aptamers open up possibilities for the development of aptamer based food and medical diagnostics.

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