Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of ...living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.
Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the ...major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.
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•Increased peroxiredoxin Tsa1 levels extend lifespan in a chaperone-dependent manner•A redox switch in Tsa1 recruits Hsp70 and Hsp104 to misfolded proteins during aging•Disaggregation of misfolded proteins requires enzyme-dependent reduction of Tsa1•Distinct chaperone pathways recognize protein aggregates on H2O2 stress and heat shock
Lifespan extension in yeast in the absence of calorie restriction is mediated by conserved redox-regulated enzymes that recruit chaperones to misfolded proteins in aggregates.
Iron-sulfur (Fe-S) clusters are essential protein cofactors whose biosynthetic defects lead to severe diseases among which is Friedreich's ataxia caused by impaired expression of frataxin (FXN). Fe-S ...clusters are biosynthesized on the scaffold protein ISCU, with cysteine desulfurase NFS1 providing sulfur as persulfide and ferredoxin FDX2 supplying electrons, in a process stimulated by FXN but not clearly understood. Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich's ataxia therapies.
Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A ...scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.
Paraffins are useful as phase change materials (PCMs) for thermal energy storage (TES) via their melting transition, Tmpt. Paraffins with Tmpt between 30 and 60 °C have particular utility in ...improving the efficiency of solar energy capture systems and for thermal buffering of electronics and batteries. However, there remain critical knowledge gaps concerning the properties of paraffin PCMs, including their long-term reliability and chemical compatibility. Therefore, we have undertaken a thorough, comprehensive study of the thermophysical properties, long-term stability and chemical compatibility of six widely useful paraffin PCMs. The PCMs investigated include three pure alkanes, nonadecane, eicosane, docosane, and three commercial blends of paraffin waxes. For each PCM, we accurately determined Tmpt, the latent heat of fusion, the density of the solid phase and the temperature dependences of the heat capacity and thermal conductivity. For the first time, we show the thermal stability of the PCMs after 3000 melt-freeze cycles, and their chemical compatibilities with 17 different metallic and plastic materials used for encapsulation and in composites and fillers. These results provide necessary information to improve energy modeling and analysis for existing and emerging TES applications, and guide the selection of reliable paraffin PCMs and encapsulation materials for such applications.
•Six PCMs studied are suitable for solar thermal and passive cooling applications.•All essential thermophysical properties and thermal stability of PCMs are measured.•Paraffin PCMs are found to be stable for over 3000 thermal cycles.•The chemical compatibilities of PCMs with 17 different materials are reported.•Properties from suppliers of commercial paraffins might not be accurate.
The NRF2 transcription factor regulates a major environmental and oxidative stress response. NRF2 is itself negatively regulated by KEAP1, the adaptor of a Cul3-ubiquitin ligase complex that marks ...NRF2 for proteasomal degradation by ubiquitination. Electrophilic compounds activate NRF2 primarily by inhibiting KEAP1-dependent NRF2 degradation, through alkylation of specific cysteines. We have examined the impact on KEAP1 of reactive oxygen and nitrogen species, which are also NRF2 inducers. We found that in untreated cells, a fraction of KEAP1 carried a long range disulfide linking Cys226 and Cys613. Exposing cells to hydrogen peroxide, to the nitric oxide donor spermine NONOate, to hypochlorous acid, or to S-nitrosocysteine further increased this disulfide and promoted formation of a disulfide linking two KEAP1 molecules via Cys151. None of these oxidants, except S-nitrocysteine, caused KEAP1 S-nitrosylation. A cysteine mutant preventing KEAP1 intermolecular disulfide formation also prevented NRF2 stabilization in response to oxidants, whereas those preventing intramolecular disulfide formation were functionally silent. Further, simultaneously inactivating the thioredoxin and glutathione pathways led both to major constitutive KEAP1 oxidation and NRF2 stabilization. We propose that KEAP1 intermolecular disulfide formation via Cys151 underlies the activation of NRF2 by reactive oxygen and nitrogen species.
CKD and Nonalcoholic Fatty Liver Disease Targher, Giovanni, MD; Chonchol, Michel B., MD; Byrne, Christopher D., MB BCh
American journal of kidney diseases,
10/2014, Letnik:
64, Številka:
4
Journal Article
Recenzirano
The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the ...presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease.
Organic phase change materials (PCMs) have many properties that make them desirable for integration in latent-heat solar thermal energy storage (TES) systems operating in the ambient-to-moderate ...temperature range, but there are significant gaps concerning their material properties, and their reliability. We present a comprehensive study of thermal and related properties (transition temperature, transition enthalpy change, heat capacity, thermal conductivity, thermal diffusivity, density), thermal stability (on cycling through the transition up to 3000 times) and chemical stability (when in contact with 16 common containment materials at 75°C) for six organic phase change materials: decanoic acid (aka capric acid, CH3(CH2)8COOH), dodecanoic acid (aka lauric acid, CH3(CH2)10COOH), tetradecanoic acid (aka myristic acid, CH3(CH2)12COOH), hexadecanoic acid (aka palmitic acid, CH3(CH2)14COOH), octadecanoic acid (aka stearic acid, CH3(CH2)16COOH) and 1-octadecanol (CH3(CH2)17OH). All show melting transitions in the temperature range 30–70°C which is suitable for solar thermal applications, with substantial enthalpy changes (>145Jg-1), and all are thermally stable over 3000 cycles. These materials all have significant potential for solar thermal energy storage applications.
•Reliable thermal energy storage materials.•Moderate temperature range (30–70°C), suitable for solar thermal applications.•Comprehensive thermophysical properties of phase change materials (PCMs).•PCMs thermally stable over 3000 cycles.•Chemical compatibility results for 6 PCMs with 16 different containment materials.
In the context of large-eddy simulation (LES) of Diesel engine combustion, two LES combustion models are proposed. Their ability to predict autoignition delays and heat release of an autoigniting ...liquid α-methylnaphthalene/n-decane jet injected into a constant-volume chamber under Diesel-like conditions is assessed. These models retain the tabulation of a complex chemistry scheme using autoigniting homogeneous reactors (HR) at constant pressure. This allows accounting for the chemical complexity of heavy hydrocarbon fuels over the wide range of conditions representative for Diesel engines, at comparatively low CPU time overhead. The tabulated homogeneous reactor (THR) approach assumes the local structure of the reaction zone to be that of an HR, while the approximated diffusion flame (ADF) approach is based on autoigniting strained diffusion flames. Two variants of each approach are considered, either neglecting sub-grid-scale mixture fraction variance (THR and ADF models), or accounting for it via a presumed β-PDF (THR-pdf and ADF–PCM models). LES results indicate that the ADF model assuming diffusion flame structures tends to predict faster propagation of the combustion toward less reactive mixture fractions then the THR model. Moreover, neglecting the mixture fraction fluctuations strongly overestimates initial experimental heat release rates after autoignition. Comparison between models shows that this assumption yields higher reaction rates and temperature levels close to the stoichiometric mixture fraction zones. Predictions in terms of autoignition are remarkably close with all models, and exhibit very few variations from one realization to the other. Variations in global heat release rate become more apparent for different realizations at later instants, in relation to the interaction of large flow scales with combustion.
•The BeeBox automatically records feeding time and occurrence in insects.•This reveals circadian rhythm in feeding in bees.•This rhythm is lost in animals kept in constant light.•Constant light also ...induces higher mortality.
In honey bees, most studies of circadian rhythms involve a locomotion test performed in a small tube, a tunnel, or at the hive entrance. However, despite feeding playing an important role in honey bee health or fitness, no demonstration of circadian rhythm on feeding has been performed until recently. Here, we present the BeeBox, a new laboratory platform for bees based on the concept of the Skinner box, which dispenses discrete controlled amounts of food (sucrose syrup) following entrance into an artificial flower. We compared caged groups of bees in 12 h-12 h light/dark cycles, constant darkness and constant light and measured average hourly syrup consumption per living bee. Food intake was higher in constant light and lower in constant darkness; mortality increased in constant light. We observed rhythmic consumption with a period longer than 24 h; this is maintained in darkness without environmental cues, but is damped in the constant light condition. The BeeBox offers many new research perspectives and numerous potential applications in the study of nectar foraging animals.
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