Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1.

Inhibition of checkpoint kinase 1 (Chk1) has shown to overcome resistance to poly (ADP-ribose) polymerase (PARP) inhibitors and expand the clinical utility of PARP inhibitors in a broad range of human cancers. Pristimerin, a naturally occurring pentacyclic triterpenoid, has been the focus of intensive studies for its anticancer potential. However, it is not yet known whether low dose of pristimerin can be combined with PARP inhibitors by targeting Chk1 signaling pathway. In this study, we investigated the efficacy, safety and molecular mechanisms of the synergistic effect produced by the combination olaparib and pristimerin in TP53-deficient and BRCA-proficient cell models. As a result, an increased expression of Chk1 was correlated with TP53 mutation, and pristimerin preferentially sensitized p53-defective cells to olaparib. The combination of olaparib and pristimerin resulted in a more pronounced abrogation of DNA synthesis and induction of DNA double-strand breaks (DSBs). Moreover, pristimerin disrupted the constitutional levels of Chk1 and DSB repair activities. Mechanistically, pristimerin promoted K48-linked polyubiquitination and proteasomal degradation of Chk1 while not affecting its kinase domain and activity. Importantly, combinatorial therapy led to a higher rate of tumor growth inhibition without apparent hematological toxicities. In addition, pristimerin suppressed olaparib-induced upregulation of Chk1 and enhanced olaparib-induced DSB marker γΗ2ΑΧ in vivo. Taken together, inhibition of Chk1 by pristimerin has been observed to induce DNA repair deficiency, which may expand the application of olaparib in BRCA-proficient cancers harboring TP53 mutations. Thus, pristimerin can be combined for PARP inhibitor-based therapy.

Effects of wearing masks during COVID-19 pandemic on the composition and diversity of skin bacteria and fungi in medical workers.

Background: Although studies have shown that wearing masks can affect the skin microbiome, more detailed and comprehensive research on wearing masks needs to be further explored. Objective: This study aimed to characterize the influence of mask wearing on the diversity and structural characteristics of the facial skin microbial community of medical staff during the COVID-19 pandemic by means of metagenomic sequencing (mNGS). Methods: A total of 40 samples were taken by swabbing the cheek in the 2 × 2 cm2 area before and after wearing the masks. DNA was extracted for metagenomic sequencing. Results: A statistically significant decrease was found in the α diversity between BN and AN groups and between B2 h and A2 h groups. BN and AN mean groups before and after 8 h of wearing the medical protective mask (N95), including 10 volunteers, respectively. B2 h and A2 h mean groups before and after 8 h of wearing masks, including 10 volunteers changing mask every 2 h, respectively. The ß diversity was found to be statistically reduced between BS and AS groups (p = 0.025), BN and AN groups (p = 0.009), and B2 h and A2 h group (p = 0.042). The fungal beta diversity was significantly decreased in every group before and after wearing masks. The main bacteria on the face before and after wearing masks were Cutibacterium (68.02 and 71.73%). Among the fungi, Malassezia predominated the facial skin surface before and after wearing masks (35.81 and 39.63%, respectively). Conclusion: Wearing different types of masks and changing masks according to different frequency will have different effects on the facial skin's microbiota.