Design, synthesis and mechanism study of coumarin-sulfonamide derivatives as carbonic anhydrase IX inhibitors with anticancer activity.

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC50 value of 6.01 ± 0.81 µM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

Enzyme-Powered Tubular Microrobotic Jets as Bioinspired Micropumps for Active Transmembrane Drug Transport.

In nature, there exist a variety of transport proteins on cell membranes capable of actively moving cargos across biological membranes, which plays a vital role in the living activities of cells. Emulating such biological pumps in artificial systems may bring in-depth insights on the principles and functions of cell behaviors. However, it poses great challenges due to difficulty in the sophisticated construction of active channels at the cellular scale. Here, we report the development of bionic micropumps for active transmembrane transportation of molecular cargos across living cells that is realized by enzyme-powered microrobotic jets. By immobilizing urease onto the surface of a silica-based microtube, the prepared microjet is capable of catalyzing the decomposition of urea in surrounding environments and generating microfluidic flow through the inside channel for self-propulsion, which is verified by both numerical simulation and experimental results. Therefore, once naturally endocytosed by the cell, the microjet enables the diffusion and, more importantly, active transportation of molecular substances between the extracellular and intracellular ends with the assistance of generated microflow, thus serving as an artificial biomimetic micropump. Furthermore, by constructing enzymatic micropumps on cancer cell membranes, enhanced delivery of anticancer doxorubicin into cells as well as improved killing efficacy are achieved, which demonstrates the effectiveness of the active transmembrane drug transport strategy in cancer treatment. This work not only extends the applications of micro/nanomachines in biomedical fields but also provides a promising platform for future cell biology research at cellular and subcellular scales.

Prevalence of myopia and uncorrected myopia among 721 032 schoolchildren in a city-wide vision screening in southern China: the Shantou Myopia Study.

AIMS: To explore the prevalence and risk factors for myopia and uncorrected myopia in schoolchildren in southern China. METHODS: The government-led Shantou Myopia Study was conducted from September 2020 to June 2021. Non-cycloplegic refraction was performed. Uncorrected visual acuity (UCVA) was measured along with presenting visual acuity if participants wore spectacles. Spherical equivalent refraction (SER) is defined as the spherical dioptres added to half of the cylindrical dioptres. Myopia is defined as SER <-0.50 dioptre with UCVA of <20/20 in at least one eye. RESULTS: This study enrolled 724 828 schoolchildren (77.8% of all schoolchildren in Shantou) from 901 schools. Data from 721 032 schoolchildren (99.5%) were analysed (mean age 11.53±3.13 years, 6-20 years, 373 230 boys and 347 802 girls). Among them, 373 459 (51.8%) had myopia: 37.1% of 465 696 children in primary schools, 75.4% of 170 164 children in junior high schools and 84.8% of 85 172 children in senior high schools. The prevalence of myopia increases non-linearly with age. Older age, female and urban living environment were independently associated with myopia prevalence and myopic SER. Among the 373 459 children with myopia, 60.0% had no refractive correction: 74.9%, 53.9% and 35.5% in primary, junior high and senior high schools, respectively. CONCLUSION: The overall prevalence of myopia among schoolchildren in Shantou was 51.8%, higher than the national average in China. The proportion of uncorrected myopia is high, especially in primary schools. Our results indicate the need for public education on eye care among schoolchildren even in a municipal city.