SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3.

Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 is an enzyme accounting for removing acetylated lysine residues from target proteins by consuming NAD+, but its role remains elusive in ferroptosis and activating ATF3. In this study, we found SIRT1 was activated during the process of RSL3-induced glioma cell ferroptosis. Moreover, the glioma cell death was aggravated by SIRT1 activator SRT2183, but suppressed by SIRT inhibitor EX527 or when SIRT1 was silenced with siRNA. These indicated SIRT1 sensitized glioma cells to ferroptosis. Furthermore, we found SIRT1 promoted RSL3-induced expressional upregulation and nuclear translocation of ATF3. Silence of ATF3 with siRNA attenuated RSL3-induced increases of ferrous iron and lipid peroxidation, downregulation of SLC7A11 and GPX4 and depletion of cysteine and GSH. Thus, SIRT1 promoted glioma cell ferroptosis by inducting ATF3 activation. Mechanistically, ATF3 activation was reinforced when RSL3-induced decline of NAD+ was aggravated by FK866 that could inhibit NAD + synthesis via salvage pathway, but suppressed when intracellular NAD+ was maintained at higher level by supplement of exogenous NAD+. Notably, the NAD + decline caused by RSL3 was enhanced when SIRT1 was further activated by SRT2183, but attenuated when SIRT1 activation was inhibited by EX527. These indicated SIRT1 promoted ATF3 activation via consumption of NAD+. Finally, we found RSL3 activated SIRT1 by inducing reactive oxygen species-dependent upregulation of AROS. Together, our study revealed SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via activation of ATF3-dependent inhibition of SLC7A11 and GPX4.

De Novo Biosynthesis of Polydatin in Saccharomyces cerevisiae.

Polydatin, with better structural stability and biological activities than resveratrol, is mainly extracted from the traditional Chinese medicinal plant Polygonum cuspidatum. In this study, based on the transcriptome analysis of P. cuspidatum, we identified the key glycosyltransferase of resveratrol and achieved the biosynthesis of polydatin from glucose by incorporation with the resveratrol biosynthesis module, UDP-glucose supply module, and glycosyltransferase expression module. Through metabolic engineering and fermentation optimization, the production of polydatin reached 545 mg/L, and the dry cell weight was 27.83 mg/g DCW, which was about twice that of extracted from the P. cuspidatum root (11.404 mg/g DCW). Therefore, it is possible to replace the production mode of polydatin from plant extraction to microbial chassis in the future.

Application value and challenge of traditional Chinese medicine carried by ZIF-8 in the therapy of ischemic stroke.

Stroke is a group of major diseases that cause death or disability in adults, with high incidence and lack of available therapeutic strategies. Although traditional Chinese medicine (TCM) has continuously achieved good effects in the therapy of stroke while there is still not convincing due to the limitation of blood-brain permeability, as well as the individual differences in usage and dosage. With the improvement of nanotechnology, TCM nanopreparation has gradually become a research hotspot in various fields due to its advantages in permeating the blood-brain barrier, targeting delivery, enhancing sustained-release drug delivery, changing the distribution in the body, and improving bioavailability. Zeolitic imidazolate framework-8 (ZIF-8) is an ideal nano-drug delivery system for adsorption, catalysis, and drug loading, which is a biocompatible metal-organic framework framed by 2-methylimidazole and zinc ions. At present, ZIF-8 was wildly used in the treatment of ischemic stroke. However, challenges remain persists for its clinical application, such as preparation technology, detection technology in vivo, targeting specificity, safety and stability, and so forth. Therefore, more efforts need to overcome the above problems to develop the application of TCM nanopreparations in the therapy of ischemia/reperfusion in the future.