Westzhu4287

Oral insulin delivery has revolutionized diabetes treatment, but challenges including degradation in the gastrointestinal environment and low permeation across the intestinal epithelium remain. Herein, to overcome these barriers, we developed a novel biodegradable nanocomposite microsphere embedded with metal-organic framework (MOF) nanoparticles. An iron-based MOF nanoparticle (NP) (MIL-100) was first synthesized as a carrier with an insulin loading capacity of 35%. The insulin-loaded MIL-100 nanoparticles modified with sodium dodecyl sulfate (Ins@MIL100/SDS) promoted insulin permeation across Caco-2 monolayer models in vitro. To improve resistance to the gastric acid environment, Ins@MIL100/SDS nanoparticles were embedded into a biodegradable microsphere to construct the nanocomposite delivery system (Ins@MIL100/SDS@MS). The microspheres effectively protected the MOF NPs from rapid degradation under acidic conditions and could release insulin-loaded MOF NPs in the simulated intestinal fluid. After the oral administration of Ins@MIL100/SDS@MS into BALB/c nude mice, increased intestinal absorption of the insulin was detected compared to the oral administration of free insulin or Ins@MIL100/SDS. Furthermore, significantly enhanced plasma insulin levels were obtained for over 6 h after oral administration of Ins@MIL100/SDS@MS into diabetic rats, leading to a remarkably enhanced effect in lowering blood glucose level with a relative pharmacological availability of 7.8%. Thus, the MOF-nanoparticle-incorporated microsphere may provide a new strategy for effective oral protein delivery.Two novel polycyclic polyprenylated acylphloroglucinols (PPAPs), garcibractinones A (1) and B (2), as well as three known analogues doitunggarcinones A-B (3-4) and garcibracteatone (5) were isolated from Garcinia bracteata fruits. Their structures were elucidated by comprehensive spectroscopic methods and single crystal X-ray diffraction. Compounds 1 and 2 possess an unprecedented caged tricyclo-[4.4.1.11,4] dodecane skeleton, and their biosynthetic pathways are also proposed. Compounds 1-2 were tested for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages.Self-organization in mono- and bilayers on HOPG of two groups of benz[5,6]acridino[2,1,9,8-klmna]acridine derivatives, namely, 8,16-dialkoxybenzo[h]benz[5,6]acridino[2,1,9,8-klmna]acridines with an increasing alkoxy substituent length and 8,16-bis(3- or 4- or 5-octylthiophen-2-yl)benzo[h]benz[5,6]acridino[2,1,9,8-klmna]acridines, i.e., three positional isomers of the same benzoacridine, is investigated by scanning tunneling microscopy. The layers were deposited from a solution of the adsorbate (in hexane or dichloromethane) and imaged ex situ at molecular resolution. In all cases, the resulting two-dimensional (2D) supramolecular organization is governed by the interactions between large, fused heteroaromatic cores that form densely packed rows separated by areas covered by substituents. In 8,16-dialkoxybenzo[h]benz[5,6]acridino[2,1,9,8-klmna]acridines, the alkoxy substituents, separating the rows of densely packed cores, are interdigitated. An increasing substituent length leads to an intuitively expected inD supramolecular structures.The drug-target protein interaction is the basis of drug screening and precise therapy in modern clinical medicine. How to acquire the information about the drug-target protein interaction in single living cell is a great challenge due to the shortage of efficient methods. Here we propose a new strategy for in situ studying the drug-target protein interaction in single living cells based on the competition of candidate drugs to the fluorescent probe-target complexes and fluorescence correlation spectroscopy (FCS) with a microfluidic chip. In this study, we used ABL kinase (target) as a model and synthesized a fluorescent probe (Cy3-dasatinib) with an affinity to the target using ABL inhibitor dasatinib as a precursor. We systematically investigated the association of the probe with targets and the dissociation of the drug-target complexes in the presence of candidate drug. We presented a new parameter IC50 (τD) to assess the inhibitory effect of drugs on the basis of the changes in the characteristic diffusion time (τD) and the binding ratio (y) of fluorescent probes during the drug competition process in living cells. We found a remarkable difference of IC50 (τD) values in living cells and in solutions, suggesting it is quite necessary to evaluate the drug-target interactions in living cells. Compared with current methods, our approach can be used to in situ and real-time study the drug-target interaction in living cells, and it may become a promising and universal tool for in situ drug research at molecular level.In recent years, self-enhanced tris(bipyridine) ruthenium(II)-based luminescence systems have achieved great development in electrochemiluminescence (ECL) but are seldom mentioned in chemiluminescence (CL). Herein, a self-enhanced CL luminophore with excellent CL behavior was synthesized by covalently cross-linking tris(4,4'-dicarboxylic acid-2,2'-bipyridyl) ruthenium(II) dichloride ([Ru(dcbpy)3]Cl2) with branched polyethylenimine (BPEI) in one molecule (BPEI-Ru(II)), which then self-assembled into nanoparticles (BRuNPs). The nanoparticles exhibited stable and strong CL emission with potassium persulfate (K2S2O8) as the oxidant. After the redox reaction between K2S2O8 and BRuNPs, and the subsequent intramolecular electron-transfer reaction, excited state luminophores were generated to emit light. This self-enhanced CL system shortened the electron transfer distance and reduced energy loss, thus improving the luminous efficiency. In addition, the CL lifetime of BRuNPs/K2S2O8 was longer than classical luminophores such as N-(4-aminobutyl)-N-ethylisoluminol (ABEI), indicating the potential application of this system in CL imaging. Selleck Smoothened Agonist Surprisingly, Ag+ was found to greatly improve the CL efficiency of BRuNPs/K2S2O8 by catalyzing the decomposition of K2S2O8 to generate SO4•-. On the basis of the enhancement effect of Ag+, a simple and rapid CL method was proposed for Ag+ detection. The chemosensor showed a wide linear range from 25 to 3000 nM and low detection limit of 9.03 nM, as well as good stability and excellent selectivity. More importantly, this result indicated that Ag+ can be used as a coreaction accelerator to develop a ternary self-enhanced CL system, BRuNPs/K2S2O8/Ag+.Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.Gold nanoplates (AuNPLs) enable the gap-mode configuration of tip-enhanced Raman spectroscopy (TERS). This allows for low-concentration molecular sensing and high-resolution imaging. Compared with non-gap-mode TERS, the gap plasmon provides significantly higher enhancement factors. In addition, AuNPLs exhibit a lightning rod or edge effect, further enhancing the laser field and increasing the spectroscopic sensitivity. In this study, we investigate the relationship between the thickness of AuNPLs and the intensity of the spontaneous Raman signal produced by 4-nitrobenzenethiol, a reporter molecule used in TERS. Our experimental and theoretical results show that the intensity of TERS spectra increases with an increase in the thickness of the AuNPLs. This study of the thickness dependence of AuNPL allows us to find a configuration with maximal nanoplasmonic effects. Moreover, the electromagnetic interaction of the AuNPL with the tip, positioned near the AuNPL's edge, results in a plasmonic nanoantenna configuration for field enhancement, with important promise for future applications to nanobioimaging and biosensing.We describe the total synthesis of epoxyquinoid natural products (+)-pestalofone A and (+)-iso-A82775C. The synthesis of (+)-16-oxo-iso-A82775C, the putative biosynthetic precursor of pestalofone C, is also presented. The allene moiety present in (+)-iso-A82775C and (+)-16-oxo-iso-A82775C was constructed from the ketodiene-yne group via a biosynthetically relevant sequence involving a conjugate reduction and a base-catalyzed tautomerization. Attempted Diels-Alder reaction-based dimerizations of (+)-16-oxo-iso-A82775C and (+)-iso-A82775C toward pestalofones B and C are also described.An efficient three-step synthesis of a new heterocyclic system is described wherein the 2H-bis([1,2,3]triazolo)[5,1-a4',5'-c]isoquinoline ring system is elaborated using a simple synthetic strategy. The approach permits the preparation of target compounds in high yields using readily available arylhydrazines and o-alkynylbenzaldehydes as starting materials. The photophysical properties of the prepared heterocycles were studied to demonstrate that the prepared compounds are attractive blue-emitting fluorophores, exhibiting quantum yields up to 98% and Stokes shifts up to 67 nm. A strong effect of the steric hindrance on the absorption and emission spectra was revealed.Understanding the coalescence of particle-laden bubbles is crucial to our understanding of the role of particles in stabilizing liquid foams. In this work, the coalescence of microparticle-laden bubbles is studied experimentally using high-speed photography. In particular, the interparticle forces in the neck region during the early stage of bubble coalescence are calculated. The results indicate that a monolayer of silica particles coating the bubble surfaces hinders the growth dynamics of the air neck formed between the coalescing bubbles. We postulate that the decrease in the growth dynamics is due to the surface pressure caused by the particle interaction after the initiation of bubble coalescence. We identify that the apparent surface tension in the neck region increases with time for particle-laden bubbles and is lower for larger particle sizes. These findings enhance our understanding of the role of particles on the dynamics of fast deforming interfaces.Exploration of catalysts is the primary focus of the electrochemical nitrogen reduction reaction (NRR). However, cost-effective materials are rarely reported. Herein, we report a composite consisting of a three-dimensional nanoporous CuO structure decorated with PdAgCu alloy nanoparticles (abbreviated as PdAgCu/CuO composites) as a highly effective catalyst. Compared with the nanoporous PdAgCu alloy and PdCu/CuO and Cu/CuO composites, PdAgCu/CuO composites exhibit much superior NRR catalytic activity with a high NH3 production rate of 40.4 μg h-1 mgcat-1. In addition, PdAgCu/CuO composites show good catalytic stability for NRR. The superior NRR performance of PdAgCu/CuO composites can be ascribed to the synergistic effects of metals and metal oxides, which are highly significant for the exploration of efficient catalysts for NRR.