Latest ArticlesWe reported the characterization of a novel brassicicene diterpene biosynthetic gene cluster, which contains a unique α-ketoglutarate-dependent dioxygenase (αKGD) enzyme, AbnI. Our findings revealed that AbnI demonstrates remarkable substrate promiscuity and is capable of activating multiple sites on both 5–8–5 and 5–9–5 brassicicene skeletons, resulting in skeleton modifications and an unexpected ring system rearrangement. These results suggested the potential utility of AbnI as an enzymatic tool for terpene CH functionalization. In addition, the catalytic mechanism of AbnI and its potential ecological implications were discussed.
Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C–H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability. Of them, compound 6b displayed a moderate anti-human coronavirus OC43 (HCoV-OC43) potency and blocked the viral entry stage through a host mechanism of action. Using chemoproteomic techniques, both transmembrane serine protease 2 (TMPRSS2) and scavenger receptor class B type 1 (SR-B1) proteins, which act as host cofactors of viral entry, were identified to be the direct targets of 6b against HCoV-OC43. Furthermore, 6b may deactivate the TMPRSS2 by inducing a change in protein conformation, rather than binding to its catalytic center, thus suppressing the viral membrane fusion. Accordingly, our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against human β-coronavirus, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The fascinating chemical structure and broad application prospect of Keggin-type polyoxometalates (POMs) have attracted many chemists to explore and discover continuously. Unlike the traditional Keggin, larger metal atomic radius, higher metal coordinated numbers, lower metal valence states and other features allow the group IVB metal-based Keggin (IVB-Keggin) more space and unknown in terms of structure and performance. Herein, density functional theory (DFT) calculations were performed to explore the influences including cores, shells, caps, and terminal ligands, et al. on IVB-Keggin, and analyze the possibility of novel structure synthesis. From the perspective of multi-layer onion-like clusters, molecular energy level, host-guest interaction energy, surface charge and covalent bond polarity can be further adjusted to achieve the oriented design of functional IVB-Keggin. These insights are expected to provide theoretical support for experimental synthesis, opening a new perspective to understand the growth of Keggin.
Hydroxylation of steroid core is critical to the synthesis of steroid drugs. Direct sp3 C–H hydroxylation is challenging through chemical catalysis, alternatively, fungal biotransformation offers a possible solution to this problem. However, mining and metabolic engineering of cytochrome P450 monooxygenases (CYPs) is usually regarded as a more eco-friendly and efficient strategy. Herein, we report the mining and identification of a new steroid CYP (CYP68BE1) from Beauveria bassiana by transcriptomics, heterologous expression, in vivo and in vitro functional characterization. The catalytic promiscuity of CYP68BE1 was explored, and CYP68BE1 showed promiscuously and catalytically versatile, which is qualified for monohydroxylation on C11α, C1α, C6β and dihydroxylation on C1β, 11α and C6β, 11α of six steroids, leading to the production of key steroid intermediates required in the industrial synthesis of some indispensable steroid drugs. Molecular dynamics simulations were performed, revealing the molecular basis of different binding orientations of CYP68BE1 with different substrates. The discovery of CYP68BE1 offers a promising biocatalyst for enriching the steroid structural and functional diversity, which also can be applied to biosynthesize valuable steroid drug intermediates.
A novel cationic Pt(Ⅱ) complex 2 with 2-(2,4-difluorophenyl)pyridine as the cyclometalating ligand and 1,10-phenanthroline as the auxiliary ligand has been synthesized and fully characterized. This complex exhibits much higher aggregation-induced phosphorescent emission activity than that of a non-fluorinated complex 1 in CH3CN/H2O. The complex 2 demonstrates efficient detection on picric acid (PA) in CH3CN/H2O, providing a high quenching constant (KSV = 2.3 × 104 L/mol) and a low limit of detection (LOD = 0.26 µmol/L). In addition, complex 2 shows high selectivity for detection of PA in real water samples. Density functional theory calculations and proton nuclear magnetic resonance spectra suggest that the detection mechanism is attributed to the photo-induced electron transfer.
Alginate is a natural polysaccharide polymer. Hydrogel filtration membranes prepared from alginate show excellent fouling resistance and controllable separation performance, but poor mechanical properties limit the use of algae hydrogels. In this study, Ba2+/Ca2+ co-crosslinked alginate (Ba/CaAlg) hydrogel membrane was prepared by cross-linking sodium alginate with a blend aqueous solution of barium ions and calcium ions, and the membrane was applied to the separation of dyes/salts from dyeing wastewater. Compared with the CaAlg membrane, the Ba/CaAlg hydrogel membrane exhibited more stable structure, and the mechanical properties and salt tolerance of the membrane were significantly improved. The flux of Ba/CaAlg membrane for methyl blue/sodium chloride mixed solution reached 43.5 L m−2 h−1, which was significantly higher than that of CaAlg membrane. Besides, the Ba/CaAlg membrane showed higher dye rejection (>99.6%) and lower salt rejection (<8.2%). The structure of Ba/CaAlg membrane was preliminarily simulated by molecular dynamics, and the pore size and distribution of the membrane were calculated. The Ba/CaAlg membrane has a broad application prospect in dyes/salts separation.
Metal–organic framework (MOF) is a periodic sexual network structure with large surface area and high porosity, which is assembled by inorganic nodes and organic ligands through coordinate covalent bond. MOFs have the advantages of controllable pore size and shape, large specific surface area, easy modification and more active sites. In addition, MOF based nanoenzymes display excellent enzyme catalytic activity due to their special structure and multiple exposed metal active sites, controlling the production of reactive oxygen species (ROS) in cells or the body, and thus regulating the polarization of macrophage. This article reviews the mechanism of MOF material regulating macrophage polarization and the function of macrophages with different phenotypes. By utilizing the excellent properties of MOFs and the advantages of combining them with bioactive materials, we have discovered their excellent applications in the treatment of inflammatory diseases. Finally, we discussed the current challenges and prospects faced by MOF based composite materials. We expect that the research in this developing field will play a more important role in combating inflammatory diseases in the field of nanomedicine.
Staphylococcal enterotoxin A (SEA) derived from Staphylococcus aureus, as a superantigen, shows potential for cancer immunotherapy, but systemic immunotoxicity restricts its clinical application. Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity. Here, we constructed an iRGD peptide (H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH2) modified nanoparticle (iDPP) to deliver plasmids encoding SEA for melanoma treatment. The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells (BMDCs) in vitro. In the subcutaneous B16-F10 melanoma model, the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration, thereby considerably decreased melanoma growth. Meanwhile, no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo. Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.
The clinical benefit of combination therapy is significant, but it is not easy to define the mechanism of complexity and diversity. Previous studies illustrate that phillygenin (Phi) binds in the allosteric inhibit pocket of protein kinase B (AKT), and swertiamarin (Swe) acts on the pleckstrin homology (PH) domain of AKT. However, the combined synergistic effect of relieving the inflammatory response has yet to be elucidated. Based on high sensitivity, specificity and fast-responsibility fluorescent sensors, the Förster resonance energy transfer (FRET) technique offers a route to provide clear insights into physiological and pathological processes. In the study, molecular docking, the fluorescent probes of Phi and Swe for FRET were designed and synthesized. FRET analysis shown that Swe and Phi concurrently acted on the PH domain and allosterically inhibited pocket of AKT, respectively. The combination of Swe and Phi significantly increased the heat stability of AKT and decreased protease-induced degeneration. In lipopolysaccharides (LPS)-induced mice and cells, the combination arrested AKT activation, nuclear factor kappa-B (NF-κB) phosphorylation, and the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8. In conclusion, FRET revealed Phi and Swe concurrently targeted AKT on different domains and the combination of Phi and Swe enhanced the anti-inflammatory effect.
Ursolic acid (UA) is a naturally occurring ursane triterpenoid, which exhibits a wide range of unique biological activities. To clarify its mechanism of action (MOA), a series of fluorescent derivatives of UA (5a–c) were designed and synthesized by conjugation with 7-nitrobenzo-2-oxa-1,3-diazole (NBD) fluorophore. Among them, 5c exhibited similar anti-proliferative activity with UA against HCT116 cells (half maximal inhibitory concentration (IC50) = 9.21 ± 0.50 µmol/L). Cell imaging experiment indicated that 5c was rapidly taken up in HCT116 cells in a dose and time-dependent manner. Then, 5c was found to localize in endoplasmic reticulum (ER), lysosomes, and mitochondria, but not in nucleus of HCT116 cells by confocal microscopy studies. Preliminary MOA proved that UA induced autophagy with a unique intracellular distribution mechanism involving ER and lysosome. In all, our work provides new clues for revealing the molecular mechanism of UA as an antitumor agent.
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