An overview of PROTACs: a promising drug discovery paradigm.

Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin-proteasome system. Currently, about 20-25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.

Effects of Serum Triglycerides on Prostate Cancer and Breast Cancer Risk: A Meta-Analysis of Prospective Studies.

Epidemiological studies show conflicting results regarding the link between serum triglyceride and the risk of prostate cancer and breast cancer. Therefore, we performed a meta-analysis of prospective studies to clarify this association. We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) database to identify relevant prospective studies of the relationship between serum triglyceride and prostate cancer and breast cancer risk. Study-specific estimates adjusting for potential confounders were combined to evaluate a summary relative risks (RRs) and 95% confidence intervals (95% CIs) using a fixed- or random-effects model. A total of 11 prospective studies (619,410 subjects and 15,691 incident prostate cancer patients) and 8 prospective studies (590,878 subjects and 12,177 incident breast cancer patients) were respectively included in our meta-analysis to assess the associations of serum triglyceride with prostate cancer and breast cancer risk. The pooled adjusted RR estimates for prostate cancer and breast cancer for the highest versus the lowest exposure levels of serum triglycerides were 0.95 (95% CI: 0.87-1.04) and 0.94 (95% CI: 0.87-1.00), respectively. Additionally, a dose-response analysis revealed that serum levels of triglycerides were not associated with the risk of prostate cancer and breast cancer. We found that serum triglyceride was not related to the risk of prostate cancer and breast cancer.

[Effect of enhanced UV-B radiation on photosynthetic structure and photosynthetic characteristics of Mentha piperita].

OBJECTIVE: To reveal the effects of UV-B radiation on the growth of medical plant Mentha piperita, simulate an enhanced UV-B radiation and evaluate intensity of radiation on the photosynthesis of M. piperita. METHOD: Three different levels of UV-B radiation were set in the experiment which included: natural light control (0 W x m(-2)), light UV-B radiation stress (0.15 W x m(-2)) and heavy UV-B radiation stress (0.35 W x m(-2)). The chloroplast ultrastructure, photosynthesis indexes and chlorophyll fluorescence parameters of the M. piperita were observed under the three treatments. RESULT: Although the chloroplast ultrastructure was destroyed to some degree under the light UV-B radiation stress, F(v)/(F)m, F(v)/F(o), qP, phiPS II and ETR could resume to the comparative level of natural light control. At the same time, qN increased firstly and decreased thereafter. But under the high strength UV-B radiation stress, the photosynthetic structures were badly destroyed, which could not recover through protecting mechanism by itself. CONCLUSION: It was showed that M. piperita was able to protect photosynthetic structures by increasing respiration and dissipation when photosynthetic capacity reduced under light UV-B radiation stress. It is demonstrated that M. piperita has high adaptation to light UV-B radiation stress, which is kind of promising medical plant for area with higher UV-B radiation.