Objective To investigate the chemical constituents of the marine sponge Theonella swinhoei collected from the Xisha Islands in the South China Sea .Methods The petroleum ether and dichloromethane extract of the marine sponge T . swinhoei were purified by solvent extraction and chromatographic methods including vacuum liquid chromatography (VLC) , medium pressureliquidchromatography(MPLC),thinlayerchromatography(TLC)onsilicagel,highperformanceliquidchro-matography(HPLC) ,and Sephadex LH-20 .The chemical structures were determined by spectroscopic analysis and comparison with the reported data .Results Eight compounds were isolated and their structures were determined as cholest-7-ene-3β,5α, 6β-triol (1) ,ergosta-7 ,22-diene-3β,5α,6β-triol (2) ,25-norcycloartane-3β,6α,16β,24-tetraol (3) ,sinuflexibilin D (4) ,14-de-oxycrassin (5) ,N-(2-phenylethyl)-(9Z)-tetradecanamide(6) ,N-(2-phenylethyl)-tetradecanamide (7) ,7 ,8-dimethyl-isoallox-azine (8) .Conclusion Compounds 1～ 7 were isolated from the sponge of genus Theonella for the first time .

With the rapid development of biotechnology, therapeutic peptide has been a hot area in the central nervous system drugs due to its features of easy to design and target specificity. However, therapeutic peptide is difficult to cross the blood brain barrier into the central nervous system and target cells, coupled with its in vivo instability, which seriously restricts its application in central nervous system diseases. This review focuses on the progress of therapeutic peptides across the blood brain barrier targeting the central nervous system, compares and analyses the methods of increasing therapeutic peptides penetration, specificity and stability in combination with other molecules, in order to provide help for the development of central nervous system drugs.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.