Green and enhanced extraction of coumarins from Cortex Fraxini by ultrasound-assisted deep eutectic solvent extraction.

Green and enhanced extraction of bioactive ingredients from medicinal plants has become a hot research field, and deep eutectic solvents have been considered as a novel kind of sustainable solvents in the extraction process. In this study, hydrogen bond acceptor (choline chloride, etc.) and hydrogen bond donor (l-malic acid, etc.) were used to prepare different kinds of deep eutectic solvents to extract coumarins from Cortex Fraxini. The extraction conditions, including the composition and moisture content of deep eutectic solvents, extraction time, and liquid-solid ratio, were systematically optimized basing on the extraction yield of coumarins. To further investigate the extraction mechanism, Fourier transform infrared spectroscopy was performed, and the microstructures of Cortex Fraxini powders were observed before and after extraction using scanning electron microscope. Results showed that the novel ultrasound-assisted extraction with conditions of deep eutectic solvent containing betaine/glycerin (1:3), aqueous solution (20%), solid-liquid ratio (15 mg/mL), and extraction time (30 min) exhibited the best extraction yields for the four target coumarins and much better extraction efficiency than with conventional solvent extractions. This suggests that the new ultrasound-assisted deep eutectic solvent extraction could be used as a green and high-efficient approach for extraction of the main coumarins from Cortex Fraxini.

Construction of Mn doped Cu7S4 nanozymes for synergistic tumor therapy in NIR-I/II bio-windows.

In photothermal therapy (PTT) and chemodynamic therapy (CDT) of cancer, poor performance of nanoagents severely impaired the therapeutic effect of cancer. To solve the problem, we proposed and constructed a novel Mn doped Cu7S4 phothermal nanoagent both in the first near-infrared (NIR-I) and the second near- infrared (NIR-II) windows in this work, which exhibited high photothermal conversion efficiency of 40.3% at 808 nm (NIR-I window) and 33.4% at 1064 nm (NIR-II window), as well as outstanding pH-sensitive catalytic performance (peroxidase-like catalytic activity and Fenton-like catalytic activities). The as-prepared Mn doped Cu7S4 could be used to load chemotherapy drug doxorubicin (DOX) after modified by folic acid. Both in vitro and in vivo studies indicated that it could be used as nanoagent for chemodynamic therapy (CDT)/photothermal therapy (PTT)/ chemotherapy of cervical carcinoma. This study thus provided an NIR-I/NIR-II/pH responsive nanoagent for potential synergistic therapy of deep-seated tumors.

Multi-omics profiling of retinal pigment epithelium reveals enhancer-driven activation of RANK-NFATc1 signaling in traumatic proliferative vitreoretinopathy.

During the progression of proliferative vitreoretinopathy (PVR) following ocular trauma, previously quiescent retinal pigment epithelial (RPE) cells transition into a state of rapid proliferation, migration, and secretion. The elusive molecular mechanisms behind these changes have hindered the development of effective pharmacological treatments, presenting a pressing clinical challenge. In this study, by monitoring the dynamic changes in chromatin accessibility and various histone modifications, we chart the comprehensive epigenetic landscape of RPE cells in male mice subjected to traumatic PVR. Coupled with transcriptomic analysis, we reveal a robust correlation between enhancer activation and the upregulation of the PVR-associated gene programs. Furthermore, by constructing transcription factor regulatory networks, we identify the aberrant activation of enhancer-driven RANK-NFATc1 pathway as PVR advanced. Importantly, we demonstrate that intraocular interventions, including nanomedicines inhibiting enhancer activity, gene therapies targeting NFATc1 and antibody therapeutics against RANK pathway, effectively mitigate PVR progression. Together, our findings elucidate the epigenetic basis underlying the activation of PVR-associated genes during RPE cell fate transitions and offer promising therapeutic avenues targeting epigenetic modulation and the RANK-NFATc1 axis for PVR management.

Long Residence Time at the Vasopressin V2 Receptor Translates into Superior Inhibitory Effects in Ex Vivo and In Vivo Models of Autosomal Dominant Polycystic Kidney Disease.

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V2 receptor (V2R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V2R antagonists, but not their affinity, was correlated with the efficacy in both ex vivo and in vivo models of ADPKD. We envision that the kinetics-directed drug candidate selection and development may have general applicability for ADPKD and other therapeutic areas as well.