摘要：Acidic oligosaccharide sugar chain （AOSC）, a D-mannuronic acid oligosaccharide, derived from brownalgaepolysaccharide, has been completed Phase I clinical trial in China as an anti-Alzheimer＇s Disease （AD） drug candidate. The identification of AOSC-binding protein（s） in neurons is very important for understanding its action mechanism. To determine the binding protein（s） of AOSC in neurons mediating its anti-AD activities, confocal microscopy, affinity chromatography, and liquid chromatography-tandem mass spectrometry （LC-MS/MS） analysis were used. Confocal microscopy analysis shows that AOSC binds to SH-SY5Y cells in concentration-, time-, and temperature-dependent fashions. The AOSC binding proteins were purified by affinity chromatography and identified by LC-MS/MS analysis. The results showed that there are 349 proteins binding AOSC, including clathrin, adaptor protein-2 （AP-2） and amyloid precursor protein （APP）. These results suggest that the binding/entrance of AOSC to neurons is probably responsible for anti-AD activities.

摘要：Benzothiadiazole(BTD) has been extensively used as a building block in optical materials. In this work, a class of π-conjugated BTD-based luminogens BTD-685, BTD-580, BTD-675 and BTD-565 were designed by varying donor units and facilely synthesized by Heck coupling reaction. It was found that their emission in solid state covered the regio from orange, red to near infrared fluorescence. Investigation on photo-physical property manifested that they had strong solvatochromic behavior except symmetric 2-vinylpyridine substituted BTD-565. Crystal X-ray diffraction analysis revealed that they involved in multi weak intermolecular interactions. And loose molecular packing implied that they can be easily rearranged under external force ***, all compounds showed reversible mechanically-responsive behavior in solid state. Interestingly, the vinylpyridinecontaining BTD-565 exhibited hypochromatic mechanochromic behavior, whereas others showed bathochromic mechanochromism behavior. It was worth mentioning that BTD-675 had self-recovery behavior after grinding. The powder X-ray diffraction study showed that these chromic processes may be mainly attributed to the reversible morphological changes between crystalline and amorphous phase upon grinding or fuming. These observations suggested that the vinyl-functionalized benzothiadiazoles can be considered as a type of excellent candidates in mechanically-responsive chromic materials.

摘要：The growth plate(GP)is a crucial tissue involved in skeleton development via endochondral ossification(EO).The bone organoid is a potential research model capable of simulating the physiological function,spatial structure,and intercellular communication of native ***,mimicking the EO process remains a key challenge for bone organoid *** simulate this orderly mineralization process,we designed an in vitro sh Ca_(v)3.3 ATDC5-loaded gelatin methacryloyl(Gel MA)hydrogel model and evaluated its bioprintability for future organoid *** this paper,we report the first demonstration that the T-type voltage-dependent calcium channel(T-VDCC)subtype Ca_(v)3.3 is dominantly expressed in chondrocytes and is negatively correlated with the hypertrophic differentiation of chondrocytes during the EO ***,Ca_(v)3.3 knockdown chondrocytes loaded with the Gel MA hydrogel successfully captured the EO process and provide a bioink capable of constructing layered and orderly mineralized GP organoids in the *** results of this study could therefore provide a potential target for regulating the EO process and a novel strategy for simulating it in bone organoids.

摘要：Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene(THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan~? in vitro assays. Studies in glioblastoma cell lines showed that the most active compound ent-4g induced apoptosis and cell cycle arrest by interfering with MDM2-P53 interaction and CDK4 activation. Cells treated with ent-4g showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

摘要：Inhibition of VEGFR-2 signaling pathway is one of the most promising approaches for the treatment of cancer. In this paper, we reported the design, synthesis, and biological evaluation of a series of biphenylurea derivatives as VEGFR-2 inhibitors. Among these compounds, 39 exhibited potent inhibitory activity against VEGFR-2 both in vitro and in vivo. The antiangiogenesis activity of 39 was further confirmed by both tube formation assay and chick chorioallantoic membrane assay.

摘要：Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of *** this study,we describe the design,synthesis,and biological evaluation of a series of O-linked indoles as potent inhibitors of *** these compounds,18 showed significant anti-angiogenesis activities via VEGFR-2 in enzymatic proliferation assays,with IC50 value of3.8 nmol/L Kinase selectivity profiling revealed that 18 was a multitargeted inhibitor,and it also exhibited good potency against VEGFR-1,PDCFR-α and β.

摘要：Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer *** phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration *** we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular *** assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration ***-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,*** to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu *** differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both *** adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent *** super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

摘要：Hypoxia is a typical feature of the tumor microenvironment,one of the most critical factors affecting cell behavior and tumor ***,the lack of tumor models able to precisely emulate natural brain tumor tissue has impeded the study of the effects of hypoxia on the progression and growth of tumor *** study reports a three-dimensional(3D)brain tumor model obtained by encapsulating U87MG(U87)cells in a hydrogel containing type I *** also documents the effect of various oxygen concentrations(1%,7%,and 21%)in the culture environment on U87 cell morphology,proliferation,viability,cell cycle,apoptosis rate,and ***,it compares two-dimensional(2D)and 3D *** comparison purposes,cells cultured in flat culture dishes were used as the control(2D model).Cells cultured in the 3D model proliferated more slowly but had a higher apoptosis rate and proportion of cells in the resting phase(G0 phase)/gap I phase(G1 phase)than those cultured in the 2D ***,the two models yielded significantly different cell ***,hypoxia(e.g.,1%O2)affected cell morphology,slowed cell growth,reduced cell viability,and increased the apoptosis rate in the 3D *** results indicate that the constructed 3D model is effective for investigating the effects of biological and chemical factors on cell morphology and function,and can be more representative of the tumor microenvironment than 2D culture *** developed 3D glioblastoma tumor model is equally applicable to other studies in pharmacology and pathology.

摘要：多重耐药细菌引发的肺部感染对人类健康构成了严重威胁.细菌生物膜加剧了肺部感染的持续和复发,限制了抗生素的可及性和有效性.基于凝集素竞争策略和颗粒表面修饰策略,本研究设计了一种硫酸多粘菌素B(PMBS)的吸入粉雾剂(DPI)用于治疗肺部感染.该制剂的载体是具有高凝集素亲和性(HLA)的小分子糖(如棉子糖),可靶向细菌凝集素,限制生物膜的扩展.该制剂的粒径约为3μm,其表面褶皱程度和药物与载体的比例有关.处方F_(5)(PMBS:棉子糖=10:90)表现出最高的微细粒子分数(FPF=64.86%),表明其具备显著增强的肺部药物递送效率.通过添加棉子糖,制剂在抑制生物膜形成和清除成熟生物膜方面的效果显著提高.在急性和慢性肺部感染的大鼠模型中,相较于喷雾干燥的PMBS,处方F_(5)表现出更强的抗菌效果,并引起更低炎症反应.综上,基于HLA载体的抗生素DPI具有治疗细菌生物膜相关肺部感染的良好前景.

摘要：As we navigate the transition from the Fourth to the Fifth Industrial Revolution,the emerging fields of biomanufacturing and biofabrication are transforming life sciences and *** sectors are benefiting from a synergy of synthetic and engineering biology,sustainable manufacturing,and integrated design *** techniques such as 3D bioprinting,tissue engineering,directed assembly,and self-assembly are instrumental in creating biomimetic scaffolds,tissues,organoids,medical devices,and biohybrid *** field of biofabrication in the United Kingdom and Ireland is emerging as a pivotal force in bioscience and healthcare,propelled by cutting-edge research and *** on the production of biologically functional products for use in drug delivery,in vitro models,and tissue engineering,research institutions across these regions are dedicated to innovating healthcare solutions that adhere to ethical standards while prioritising sustainability,affordability,and healthcare system benefits.