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The main objective of this research was to evaluate the efficacy of intermittent hypoxic training (IHT) on anaerobic and aerobic capacity and swimming performance in well-trained swimmers. Sixteen male swimmers were randomly divided into a hypoxia (H) group (n = 8), which trained in a normobaric hypoxia environment, and a control (C) group (n = 8), which exercised under normoxic conditions. However, one participant left the study without explanation. During the experiment group H trained on land twice per week in simulated hypoxia (FiO2 = 15.5%, corresponding to 2,500 m a.s.l); however, they conducted swim training in normoxic conditions. Group C performed the same training program under normoxic conditions. The training program included four weekly microcyles, followed by three days of recovery. During practice sessions on land, the swimmers performed 30 second sprints on an arm-ergometer, alternating with two minute high intensity intervals on a lower limb cycle ergometer. The results showed that the training on land caused a significant (p<0.05) increase in absolute maximal workload (WRmax) by 7.4% in group H and by 3.2% in group C and relative values of VO2max by 6.9% in group H and 3.7% in group C. However, absolute values of VO2max were not significantly changed. Additionally, a significant (p<0.05) increase in mean power (Pmean) during the first (11.7%) and second (11.9%) Wingate tests was only observed in group H. The delta values of lactate concentration (ΔLA) after both Wingate tests were significantly (p<0.05) higher in comparison to baseline levels by 28.8% in group H. Opposite changes were observed in delta values of blood pH (ΔpH) after both Wingate tests in group H, with a significant decrease in values of ΔpH by 33.3%. The IHT caused a significant (p<0.05) improvement in 100m and 200m swimming performance, by 2.1% and 1.8%, respectively in group H. Training in normoxia (group C), resulted in a significant (p<0.05) improvement of swimming performance at 100m and 200m, by 1.1% and 0.8%, respectively. In conclusion, the most important finding of this study includes a significant improvement in anaerobic capacity and swimming performance after high-intensity IHT. However, this training protocol had no effect on absolute values of VO2max and hematological variables.

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

Background Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid found in certain coffee (Coffea) species, fruits (Cupuacu [Theobroma grandiflorum]), and tea (Camellia assamica, var. kucha) that has anti-inflammatory, analgesic, and neuro-locomotor properties. Recent preliminary research has also reported increased feelings of energy, reduced fatigue, and strong effects on improving focus, concentration, and motivation to exercise. The purpose of this study was to examine the safety and non-habituating effects of TeaCrine®, a nature-identical, chemically equivalent bioactive version of theacrine. Methods Sixty healthy men (mean ± SD age, height, weight: 22.9 ± 4.7 years, 183.5 ± 9.2 cm, 86.5 ± 13.7 kg) and women (22.3 ± 4.5 years, 165.2 ± 12.3 cm, 69.0 ± 17.4 kg) were placed into one of three groups: placebo (PLA, n  = 20), 200 mg TeaCrine® (LD, n  = 19) or 300 mg Teacrine® (HD, n  = 21) and ingested their respective supplement once daily for 8 weeks. Primary outcomes were fasting clinical safety markers (heart rate, blood pressure, lipid profiles, hematologic blood counts, biomarkers of liver/kidney/immune function) and energy, focus, concentration, anxiety, motivation to exercise, and POMS measured prior to daily dosing to ascertain potential tachyphylactic responses and habituation effects. Data were analyzed via two-way (group × time) ANOVAs and statistical significance was accepted at p  < 0.05. Results All values for clinical safety markers fell within normal limits and no group × time interactions were noted. No evidence of habituation was noted as baseline values for energy, focus, concentration, anxiety, motivation to exercise, and POMS remained stable in all groups across the 8-week study protocol. Conclusions These findings support the clinical safety and non-habituating neuro-energetic effects of TeaCrine® supplementation over 8 weeks of daily use (up to 300 mg/day). Moreover, there was no evidence of a tachyphylactic response that is typical of neuroactive agents such as caffeine and other stimulants.

In nature, coenzyme-independent oxidases have evolved in selective catalysis using isolated substrate-binding pockets. Single-atom nanozymes (SAzymes), an emerging type of non-protein artificial enzymes, are promising to simulate enzyme active centers, but owing to the lack of recognition sites, realizing substrate specificity is a formidable task. Here we report a metal-ligand dual-site SAzyme (Ni-DAB) that exhibited selectivity in uric acid (UA) oxidation. Ni-DAB mimics the dual-site catalytic mechanism of urate oxidase, in which the Ni metal center and the C atom in the ligand serve as the specific UA and O 2 binding sites, respectively, characterized by synchrotron soft X-ray absorption spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, and isotope labeling. The theoretical calculations reveal the high catalytic specificity is derived from not only the delicate interaction between UA and the Ni center but also the complementary oxygen reduction at the beta C site in the ligand. As a potential application, a Ni-DAB-based biofuel cell using human urine is constructed. This work unlocks an approach of enzyme-like isolated dual sites in boosting the selectivity of non-protein artificial enzymes. Single-atom nanozymes are a type of non-protein artificial enzymes and promising for mimicking enzyme active centers, but lack recognition sites to confer substrate specificity. Here, the authors report on a metal-ligand dual-site single-atom nanozyme (Ni-DAB) that mimics the dual-site catalytic mechanism of urate oxidase and has high selectivity in uric acid (UA) oxidation.

Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization. The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve) was determined at doses of 800 mg, 1,200 mg, and 1,600 mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600 mg (supratherapeutic dose), lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI). The upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI) was <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, confirming assay sensitivity. Lesinurad, at supratherapeutic doses, does not have a significant effect on the QT interval in healthy male or female subjects.

A uric acid (UA) electrochemical biosensor was constructed using ferrocene (Fc) decorated cuprous oxide (Cu 2 O) enhanced electro-active characteristics and covalently immobilized with uricase (UOx) on glassy carbon electrode (GCE). The electrochemical characteristics of the fabricated electrode was analysed by cyclic voltammetry, electrochemical impedance spectroscopy and differential pulse voltammetry (DPV). DPV studies revealed rapid response of fabricated electrode UOx/Fc/Cu 2 O/GCE towards UA in a wide concentration range of 0.1–1,000 μM with a sensitivity of 1.900 μA mM −1  cm −2 and very low detection limit of 0.0596 μM. A very low magnitude Michaelis–Menten constant (Km) value was evaluated as 34.7351 μM which indicated the chemical attraction of the enzyme towards the UA was much higher. The developed biosensor was successfully applied to detect UA in human urine samples. Moreover, reproducibility and stability studies demonstrated the fabricated UOx/Fc/Cu 2 O/GCE biosensor had high reproducibility with a RSD of 2.8% and good reusability with a RSD of 3.2%. Specificity studies results showed the fabricated biosensor had strong anti-interference ability. The improved sensor performance was attributed to the synergistic electronic properties of Cu 2 O and Fc that provided enhances delectrocatalytic activity and electron transfer. The present biosensor can be extended for use in clinical settings.

Nitrogen-doped graphene quantum dots (N-GQD) were employed along with Cu(II) ions under alkaline conditions and room temperature to synthesize nanocomposites of type Cu(II)/Cu 2 O/N-GQDs. These nanocomposites exhibit excellent stability and dispersity, and also display a peroxidase-like activity that is superior to pure Cu 2 O nanoparticles and natural peroxidase (POx). A chemiluminescence (CL) method was designed that is based on the use of uricase which oxidizes uric acid under formation of H 2 O 2 . The nanocomposites were used as a POx mimic in the luminol-H 2 O 2 CL system. Under optimized conditions, a linear relationship between CL intensity and the uric acid (UA) concentration in the range of 0.16—4.0 μM, and a detection limit of 0.041 μM (at S/ N  = 3) were obtained. The CL method was applied to the determination of UA in spiked serum and urine, and recoveries ranged from 85.0 to 121.3%. Graphical abstract Schematic presentation of synthesis strategy of Cu(II)/Cu 2 O/N-GQDs and the CL method based Cu(II)/Cu 2 O/N-GQDs for H 2 O 2 -meidated uric acid detection. The method can be used for the determination of uric acid (UA) with the detection limit of 0.041 μM.

Copper-cobalt bimetallic nitrogen-doped carbon-based nanoenzymatic materials (CuCo@NC) were synthesized using a one-step pyrolysis process. A three-channel colorimetric sensor array was constructed for the detection of seven antioxidants, including cysteine (Cys), uric acid (UA), tea polyphenols (TP), lysine (Lys), ascorbic acid (AA), glutathione (GSH), and dopamine (DA). CuCo@NC with peroxidase activity was used to catalyze the oxidation of TMB by H 2 O 2 at three different ratios of metal sites. The ability of various antioxidants to reduce the oxidation products of TMB (ox TMB) varied, leading to distinct absorbance changes. Linear discriminant analysis (LDA) results showed that the sensor array was capable of detecting seven antioxidants in buffer and serum samples. It could successfully discriminate antioxidants with a minimum concentration of 10 nM. Thus, multifunctional sensor arrays based on CuCo@NC bimetallic nanoenzymes not only offer a promising strategy for identifying various antioxidants but also expand their applications in medical diagnostics and environmental analysis of food. Graphical Abstract

A simple dual-read assay for uric acid (UA) was developed based on a combined ratiometric fluorescent and colorimetric strategy using nitrogen-doped carbon dots (N-CDs). The biosensor relies on the oxidation of UA by uricase to produce H 2 O 2 , which was then converted to • OH radicals by I - , resulting in the oxidation of o -phenylenediamine (OPD) to 2,3-diaminophenazine (DAP). In the presence of UA, the colorless biosensor system changed to yellow. Furthermore, the presence of DAP quenched the fluorescence emission of the N-CDs at 427 nm based on the inner filter effect (IFE). With increasing UA concentrations, the fluorescence intensity of the biosensor at 427 nm decreased but increased at 580 nm, demonstrating the ratiometric response. A strong linearity was observed between the fluorescence intensity ratio of DAP to N-CDs ( I 580 / I 427 ) and the corresponding UA concentration over the range 0.5−150 μM, and a limit of detection (S/N ratio of 3) of 0.06 μM was calculated. The dual-read assay was successfully employed in the quantitation of UA in human serum and urine samples, revealing its potential for measuring UA in clinical samples. Graphical abstract

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure. Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al . show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.