Recent advances in targeted protein degraders as potential therapeutic agents.

Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted protein degraders could target "undruggable targets" and overcome drug resistance through ubiquitin-proteasome pathway (UPP) and lysosome pathway. Nowadays, some bivalent degraders such as proteolysis-targeting chimeras (PROTACs) have aroused great interest in drug discovery, and some of them have successfully advanced into clinical trials. In this review, to better understand the mechanism of degraders, we elucidate the targeted protein degraders according to their action process, relying on the ubiquitin-proteasome system or lysosome pathway. Then, we briefly summarize the study of PROTACs employing different E3 ligases. Subsequently, the effect of protein of interest (POI) ligands, linker, and E3 ligands on PROTAC degradation activity is also discussed in detail. Other novel technologies based on UPP and lysosome pathway have been discussed in this paper such as in-cell click-formed proteolysis-targeting chimeras (CLIPTACs), molecular glues, Antibody-PROTACs (Ab-PROTACs), autophagy-targeting chimeras, and lysosome-targeting chimeras. Based on the introduction of these degradation technologies, we can clearly understand the action process and degradation mechanism of these approaches. From this perspective, it will be convenient to obtain the development status of these drugs, choose appropriate degradation methods to achieve better disease treatment and provide basis for future research and simultaneously distinguish the direction of future research efforts.

[The Role of Long Chain Non-coding RNA-Paupar in the Process of Bupivacaine Induced Neurotoxicity].

OBJECTIVE: To observe the expression mode and modulation effects of lncRNA-Paupar in the process of bupivacaine induced neurotoxicity. METHODS: Dorsal root ganglion (DRG) neurons were cultured and neurotoxicity model was produced on it. And the expression of lncRNA-Paupar was evaluated by qRT-PCR. Lnc-Paupar specific siRNA-P and random control group siRNA-C were constructed,200 nmol/L siRNA-P,siRNA-C were transfected into ganglion cells and the apoptosis rate of transfected cells were observed by TUNEL method. The JNK and phosphorylated JNK (p-JNK) protein expression were observed with Western blot,respectively. RESULTS: LncRNA-Paupar was significantly up-regulated during the process of bupivacaine induced neurotoxicity and siRNA mediated lncRNA-Paupar down-regulation protected DRG neurons cells from apoptosis. Both JNK and p-JNK protein were reduced in siRNA transfected cells exemplified by Western blot. CONCLUSION: LncRNA-Paupar could induced neurotoxicity through JNK pathway.

Bioavailability and antioxidant effects of a xanthone-rich Mangosteen (Garcinia mangostana) product in humans.

Oxidative damage is involved in many chronic diseases including those cited as the major causes of death in Western societies such as cardiovascular disorders and cancer. Antioxidants may prevent these degenerative processes by various mechanisms including the scavenging of free radicals. Intake of antioxidant supplements is associated with preventing oxidative damages. This study investigated the absorption and antioxidant effects of a xanthone-rich mangosteen liquid in healthy human volunteers after the acute consumption of 59 mL of the supplement. The liquid contained mangosteen, aloe vera, green tea, and multivitamins. Results indicated that alpha-mangostin and vitamins B(2) and B(5) were bioavailable, with observed C(max) at t(max) of around 1 h. The antioxidant capacity measured with the oxygen radical absorbance capacity (ORAC) assay was increased with a maximum effect of 18% after 2 h, and the increased antioxidant level lasted at least 4 h. Overall, this study demonstrated the bioavailability of antioxidants from a xanthone-rich mangosteen product and its in vivo antioxidant effects.

Novel high-throughput assay for antioxidant capacity against superoxide anion.

A novel high-throughput assay for measuring antioxidant capacity against superoxide anion has been developed and validated. In this assay, hydroethidine (HE), a fluorescent probe, is oxidized by superoxide anion generated by xanthine and xanthine oxidase and increases its fluorescence intensity. Therefore, the inhibition of loss of HE's fluorescence intensity in the presence of antioxidant is an index of antioxidant capacity. The result is expressed as superoxide dismutase (SOD) equivalent. Unlike other probes, such as tetrazolium and lucigenin, one major advantage of this assay is that the use of HE is not prone to artifact. The method was rigorously validated through linearity, precision, accuracy, and ruggedness. The linear range, limit of quantitation (LOQ), and limit of detection (LOD) are 0.22-3.75 units/mL, 0.30 unit/mL, and 0.10 unit/mL, respectively. A wide variety of phenolic compounds and fruit extracts were analyzed.