No abstract

No abstract

No abstract

Random-walk models are frequently used to model distinct natural phenomena such as diffusion processes, stock-market fluctuations, and biological systems. Here, we present a random-walk model to describe the dynamics of glucose uptake by the sodium-glucose transporter of type 2, SGLT2. Our starting point is the canonical alternating-access model, which suggests the existence of six states for the transport cycle. We propose the inclusion of two new states to this canonical model. The first state is added to implement the recent discovery that the Na+ ion can exit before the sugar is released into the proximal tubule epithelial cells. The resulting model is a seven-state mechanism with stochastic steps. Then we determined the transition probabilities between these seven states and used them to write a set of master equations to describe the time evolution of the system. We showed that our model converges to the expected equilibrium configuration and that the binding of Na+ and glucose to SGLT2 in the inward-facing conformation must be necessarily unordered. After that, we added another state to implement inhibition in the model. Our results reproduce the experimental dependence of glucose uptake on the inhibitor concentration and they reveal that the inhibitors act by decreasing the number of available SGLT2s, which increases the chances of glucose escaping reabsorption.

Nowadays the bactericidal and antimicrobial properties of silver nanoparticles, AgNPs, in addition to their cytotoxic effects, have been explored to properly modulate cell biochemistry processes in order to improve the healing of wounds. Herein we investigate the cytotoxicity and metabolic pro ling of two human cell lineages, the broblast FN1 and endothelial HUV-EC-C, planning doses of AgNPs and incubation times. Cytotoxicity assays showed consistent decrease in proliferation rates, viable cells number, and average surface areas. Metabolomics based on proton Nuclear Magnetic Resonance was successfully used to obtain quantitative and qualitative changes in metabolic events triggered by silver treatments. The metabolic pro ling provided by endo-and exometabolome revealed biochemical changes induced on treated cells compared to controls. Glycolytic pathway is up-regulated due to the elevation in glucose consumption; however, the consequent elevation in pyruvate production seems to be wasted by cells to generate energy by aerobic means that are choosing to oxidize it to acetate. Aminoacid metabolism is down-regulated, signalizing the protein degradation mechanism. Tricarboxylic Acid Cycle is also down-regulated, indicating a starvation situation once succinate was left over in the culture media.Concurrently, the ketogenic pathway is up-regulated due to the excess of acetone. Changes in pyroglutamate metabolism were detected indicating the up-regulation of glutathione biosynthesis used to equilibrate the effects induced by oxidative stress, in accordance with the N-Acetylcysteine nds.Phospholipid metabolism is down-regulated, as revealed by the changes in O-Phosphocholine and Sn-Glycerol-3-PC levels, signaling reduction in the cellular proliferation rates. To the best of our knowledge, this is the rst report describing AgNP-induced changes in the UDP-GlcNAc levels, which plays an essential role in modifying nucleocytoplasmic proteins. In summary, AgNPs can induce oxidative stress and cytotoxicity in endothelial and broblast cells, in uencing their endo-and exometabolome.