Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery.

Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.

CircSCAP Aggravates Oxidized Low-density Lipoprotein-induced Macrophage Injury by Upregulating PDE3B by miR-221-5p in Atherosclerosis.

ABSTRACT: Atherosclerosis (AS) is a major risk factor for cardiovascular disease, in which circular RNAs play important regulatory roles. This research aimed to explore the biological role of circular RNA Sterol Regulatory Element Binding Transcription Factor Chaperone (circSCAP) (hsa_circ_0001292) in AS development. Real-time PCR or Western blot assay was conducted to analyze RNA or protein expression. Cell proliferation and apoptosis were analyzed by CCK-8 assay and flow cytometry. The levels of lipid accumulation-associated indicators and oxidative stress factors were detected using commercial kits. The levels of inflammatory cytokines were examined using enzyme-linked immunosorbent assay. Intermolecular interaction was verified by dual-luciferase reporter analysis or RNA pull-down analysis. CircSCAP and phosphodiesterase 3B (PDE3B) levels were elevated, whereas the miR-221-5p level was decreased in patients with AS and oxidized low-density lipoprotein (ox-LDL)-induced THP-1 cells. CircSCAP absence suppressed lipid deposition, inflammation, and oxidative stress in ox-LDL-induced THP-1 cells. MiR-221-5p was a target of circSCAP, and anti-miR-221-5p largely reversed si-circSCAP-induced effects in ox-LDL-induced THP-1 cells. PDE3B was a target of miR-221-5p, and PDE3B overexpression largely counteracted miR-221-5p accumulation-mediated effects in ox-LDL-induced THP-1 cells. NF-κB signaling pathway was regulated by circSCAP/miR-221-5p/PDE3B axis in ox-LDL-induced THP-1 cells. In conclusion, circSCAP facilitated lipid accumulation, inflammation, and oxidative stress in ox-LDL-induced THP-1 macrophages by regulating miR-221-5p/PDE3B axis.

NPD1 inhibits excessive autophagy by targeting RNF146 and wnt/ß-catenin pathway in cerebral ischemia-reperfusion injury.

Objective: Cerebral ischemia-reperfusion (I/R) injury is a common pathological feature in ischemic stroke. Autophagy plays a key role in I/R-induced neuronal death. Neuroprotectin D1 (NPD1) is a docosahexaenoic acid derivative with neuroprotective and anti-inflammatory properties. The purpose of this study was to investigate the mediatory role of NPD1 on I/R-induced injury and to elucidate the underlying mechanisms involved in this process.Methods: An I/R injury model was established in PC12 cells induced by oxygen and glucose deprivation/reoxygenation (OGD/R). NPD1 at increasing doses (5, 10, 20, 50, 100 nM) were added to cells one hour before OGD/R. To investigate the effect of ring finger protein 146 (RFP146) deficiency in I/R injury, PC12 cells were transiently transfected with small interfering RNF146 before further experiment.Results: Compared to the controls, OGD/R-challenged cells exhibited significantly decreased cell viability, induced oxidative stress, and excessive autophagic cell death following OGD/R. Pretreatment with NPD1 protected cells against ischemic injury as evidenced by enhanced cell survival, decreased oxidative stress markers, and a lower level of autophagy compared to drug-free group. OGD/R also increased the level of RFP146 and inhibited the expression of ß-catenin in PC12 cells. NPD1 treatment promoted the production of RNF146 and ß-catenin in cells following OGD/R experiment. Moreover, RNF146 deficiency significantly inhibited ß-catenin expression and reversed the protective effects of NPD1 in OGD/R-induced cells.Conclusion: NPD1 alleviated excessive autophagy via regulating RNF146 and Wnt/ß-catenin signaling, suggesting the potential therapeutic use of NPD1 for the protection against cerebral I/R injury.

Primary nasopharyngeal polyps: a case series on a rare clinical entity.

Primary non-neoplastic polyps originating from the nasopharynx have not been reported in the English language literature. We present the clinical and histopathological features of three primary nasopharyngeal polyps. Clinical data of three patients with primary nasopharyngeal polyps treated at the Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University between 2005 and 2015 were analyzed and presented. Three male patients from 45 to 63 years presented with nasopharyngeal masses. CT or MRI examination showed nasopharyngeal space-occupying lesions. Two patients were initially diagnosed with nasopharyngeal angiofibroma and one patient with nasopharyngeal carcinoma. After surgical excision, based on the histological examination, the tissue masses were all diagnosed as inflammatory polyps. Histologically, the polyps demonstrated significant oedema, collagen deposition, leukocytic infiltration, and epithelial remodelling. Primary nasopharyngeal polyps represent a distinct clinical entity and should be considered in the differential diagnosis of nasopharyngeal masses.