Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

Long Hours' Effects on Work-Life Balance and Satisfaction.

PURPOSE: In this study, we examined whether the associations between working hours, job satisfaction, and work-life balance are mediated by occupational stress. In addition, we tested whether perceived time control helps moderate the effects of working hours and occupational stress. METHODOLOGY: Questionnaires were administered to 369 respondents working in the high-tech and banking industries. Analyses were then conducted on the data. FINDINGS: The analysis revealed significant correlations between long working hours and both occupational stress and work-life balance, as well as between occupational stress and both work-life balance and job satisfaction. In addition, the relationship between working hours and occupational stress exhibited a significantly positive interaction with perceived time control. VALUE: The results indicate the importance of giving workers greater control over working hours. We therefore recommend that labor laws should be revised as necessary to prevent excessive working hours and enhance work-time flexibility.

Syntheses of nickel (II) complexes from novel semicarbazone ligands with chloroformylarylhydrazine, benzimidazole and salicylaldehyde moieties.

This study addressed the design and syntheses of diverse ligands, which were then successfully treated with Ni (II) ion to afford a series of nickel complexes. α-Chloroformylarylhydrazine hydrochlorides contain two different functional groups. One is a strong nucleophile, and the other is a good electrophile. Therefore, it can be designed to react with several reagents to obtain diverse derivatives which can be used as ligands for metal complexes. Furthermore, benzimidazole and salicylaldehyde can provide electron donor sites, N and O electron donors, separately. Hence, the starting materials α-chloroformylarylhydrazine hydrochlorides were first treated with 2-(aminomethyl)-benzimidazole (7) to give the corresponding semicarbazides. Then, the semicarbazides 8 reacted with various substituted salicylaldehydes to afford the desired substituted-salicylaldehyde 2-aryl-4-substituted semicarbazones, which could coordinate with nickel (II) ion to give the corresponding nickel complexes.

Novel synthesis of palladium (II) complexes derived from 3-arylsydnone-4-carbaldehyde N(4)-phenylthiosemicarbazones and biological activity.

OBJECTIVES: The aim of this research is to investigate whether the oxygen atom O(6) in the sydnone ring of 3-arylsydnone-4-carbaldehyde N(4)-phenylthiosemicarbazones (HArSYTSCs, 3a-d) is a good electron donor atom upon metal complexation. Furthermore, ligands 3a-d and the corresponding palladium complexes (Pd(ArSYTSC)Cl, 4a-d) would be expected to find their potent biological activities. METHODS: The desired palladium complexes 4a-d were first synthesized from thiosemicarbazones 3a-d. Then, the antiproliferative activity of ligands 3a-d and complexes 4a-d were tested against human hepatocellular carcinoma and human cervical epithelioid carcinoma (HeLa) cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl trazolium bromide (MTT) assay. KEY FINDINGS: According to X-ray analyses, ligands 3a-d are bonded to the Pd (II) center in an O, N, S-tridentate coordination mode through sydnone carbonyl oxygen O(6), azomethine nitrogen and the thiolate sulfur atom. The carbonyl oxygen of the sydnone ring is found to be a good electron donor site upon metal complexation. Moreover, MTT assay results reveal that the palladium complexes 4a-d have greater antiproliferative activity than 5-fluorouracil. In particular, the complexes exhibit obvious better activity than the corresponding ligands 3a-d against HeLa cell. CONCLUSIONS: The results indicate that the synthesized novel palladium complexes have greater antiproliferative activity than both 5-fluorouracil and the corresponding ligands against HeLa cell. Accordingly, the study of sydnonyl complexes bearing anticancer activities may support the development of coordination chemistry.