Latest ArticlesPolyketide synthases (PKSs) are megasynthases with multiple autonomously folding domains, which operate cooperatively in the PKS assemblies to synthesize specific polyketide scaffolds. Any nonreactive intermediates tethered to acyl carrier protein (ACP) domain in the PKS will block the elongation process of polyketide chains. In this study, we systematically elucidate the editing function of fungal type Ⅱ thioesterases (TEIIs) to hydrolyze ACP domain-bounded nonreactive acyl groups, which are uploaded by substrate promiscuous fungal phosphopantetheinyl transferase. Thereof, the TEIIs encoded in gene clusters of nonreducing PKS with reductase domain exhibit universal editing function. Besides, editing function was also found for TEIIs encoded in gene clusters of highly-reducing PKS with condensation domain. Hence, the editing TEIIs with function of recovery PKS are applied to improve the yield of the fungal polyketides in vivo. Our study provides valuable insights into the editing process of fungal PKSs, highlights the crucial role of TEIIs in enhancing polyketide production and introduces a novel metabolic engineering strategy for fungal polyketide biosynthesis by leveraging the editing function of TEIIs.
The development of resistance against most of the available antibiotics has made Acinetobacter baumannii (A. baumannii) a pathogen of high risk. In this study, thirty novel berberine derivatives are rationally designed, synthesized, and evaluated for their synergistic antibacterial activities against A. baumannii. Among them, compound 2d shows the most potent synergetic effect to aztreonam against A. baumannii, including carbapenem-resistant and extended-spectrum β-lactamases-producing strains. Moreover, synergistic effects were observed for the combinations of 2d and different antibacterial used in clinical practices, indicating its potent broad-spectrum antibiotic-sensitizing effects against A. baumannii. The combination of 2d and aztreonam significantly improves the survival rates of G. mellonella larvae compared with aztreonam treatment alone. Mechanism studies indicate that 2d inhibits the drug efflux and iron acquisition of the bacteria by targeting the AdeB transporter protein, thus achieving a synergistic antimicrobial efficacy with different antibacterial agents. Therefore, berberine derivatives represent a new family of antimicrobial adjuvants against A. baumannii, with the advantage of dual-function antibacterial effect, and are worthy of further investigation.
The application of nanotechnologies in formulation has significantly promoted the development of modern medical and pharmacological science, especially for nanoparticle-based drug delivery, bioimaging, and theranostics. The advancement of engineering particle design and fabrication is largely supported by a better understanding of how their apparent characteristics (e.g., size and size distribution, surface morphology, colloidal stability, chemical composition) influence their in vivo biological performance, which raises an urgent need for practical nanoformulation methods. Based on turbulent flow mixing and the self-assembly of molecules in fluids, flash technologies emerged as effective bottom-up fabrication strategies for effective nanoformulation. Among the flash technology family, flash nanocomplexation (FNC) is considered a novel and promising candidate that can promote and optimize formulation processes in a precise spatiotemporal manner, thus obtaining excellent fabrication efficiency, reproducibility and expandability. This review presents an overview of recent advances in fabricating drug-delivery nanoparticles using FNC platforms. Firstly, brief introductions to the basic principles of FNC technology were carried out, followed by descriptions of turbulent microvolume mixers that have significantly promoted the efficiency of FNC-based fabrications. Applications of real formulation cases were then categorized according to the self-assembly-driven interactions (including electrostatic interaction, coordination interaction, hydrogen bonding and hydrophobic interaction) and discussed to reveal the progressiveness of fabricating nanoparticles and discuss how its flexibility will provide advances and replenish the philosophy of nanomedicine formulation. In the end, the commercial potential, current limitations, and prospects of FNC technology for nanoformulation will be summarized and discussed.
As a promising imaging technology, the low sensitivity of fluorine-19 magnetic resonance imaging (19F MRI) severely hinders its biomedical applications. Herein, we have developed an unprecedented rotaxane-based strategy to improve the sensitivity of 19F MRI agents. By threading the fluorinated macrocycle into 2-blade pinwheel [2]rotaxanes, the 19F longitudinal relaxation rate R1 was dramatically increased, resulting in a significant 19F MRI signal intensity enhancement of up to 79%. Through comparative molecular dynamics studies using a series of solution and solid-state 1H/19F nuclear magnetic resonance (1H/19F NMR) and molecular dynamics simulations, it was found that the formation of mechanical bonds dramatically restricts the motion of the wheel fluorines and thus increasing the R1 for higher 19F MRI sensitivity. Besides a novel strategy for improving 19F MRI sensitivity, this study has established 19F NMR/MRI as a valuable technology for monitoring the molecular dynamics of rotaxanes, which may shed new light on high-performance 19F MRI agents and molecular devices.
Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy. Dihydroartemisinin (DHA), a derivative of artemisinin, has been shown to exert anti-tumor effects through the production of reactive oxygen species (ROS) and resultant mitochondrial damage. However, clinical translation is limited by several drawbacks, such as insolubility, instability and low bioavailability. Here, based on a nanomedicine-based delivery strategy, we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium (TPP), aiming to improve bioavailability and mitochondrial targeting. DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized. Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS, which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway, leading to apoptosis. In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma. These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.
Photodynamic therapy (PDT) has garnered significant attention as a promising approach to cancer therapy, harnessing the combined benefits of localized light treatment and the accompanying host immune response. In this study, we engineered an immuno-enhanced PDT nanoplatform, denoted as HM@p-MOF (hybrid membrane@porphyrin-metal organic framework). The core porphyrin-MOF was cloaked with a hybrid membrane derived from B16F10 cancer cells and NK cells, resulting in enhanced stability. In both in vitro and in vivo experiments, our finding demonstrated that the hybrid membrane conferred dual targeting capabilities to the nanoplatform, leveraging the unique properties of the B16F10 membrane and NK membrane to augment immunogenic cell death (ICD) induced by photodynamic effects. Additionally, in conjunction with the immunomodulatory functions of the NK cell membrane, we observed an expansion of in situ immune infiltration leading to a systemic immune response. The HM@p-MOF nanoplatform exhibited the capacity to not only inhibit the growth of mouse melanoma but also suppress metastasis. This innovative HM@p-MOF nanoplatform present a viable strategy to enhance phototherapeutic efficacy for both localized and metastatic tumors. It provides a direction for the fabrication of biomimetic nanomedicines possessing immuno-modulatory function.
Long-term fluorescence monitoring of subcellular organelles is crucial for cellular physiology and pathology studies. Lipid droplets (LDs) are increasingly recognized for their involvement in various biological processes, to influence disease development through diverse behaviors However, existing LD probes face challenges in achieving high targeting and long-term monitoring due to poor photostability and long-term phototoxicity. Carbon quantum dots (CQDs) have gained prominence due to their exceptional fluorescence properties, but their prevalent blue excitation wavelength presents difficulties for long-term imaging. Herein, we synthesized red-emissive carbon quantum dot (R-CQDs) with superior photobleaching resistance and red-emission, thus enabling harmlessly fluorescence monitoring of cells longer than 3 h. In addition, R-CQD exhibits suitable amphiphilicity and remarkable solvatochromic effect, allowing rapid targeting to LDs for immediate imaging without cumbersome washing steps. Hence, R-CQD shows high performance for extended observation of dynamic LD behavior in various biological processes, which is confirmed by documenting the course of LDs during starvation as well as lipotoxicity. Compared to commercial probes, R-CQD extends live cell imaging time by at least 9-fold, facilitating the study of LD behavioral characteristics under diverse physiological or pathological conditions. This work provides a reliable fluorescence tool for tracking intercellular microenvironment dynamically thus to understand the divers biological or disease mechanism.
Deep oxidation of NO molecules to nitrate species by photocatalysis with virtually no toxic byproduct NO2 generation is a challenging task. In this study, TiO2 in-situ grows based on NH2−MIL-125(Ti) (NM-125) not only inhibited TiO2 agglomeration, but also contacted more tightly to obtain efficient interfacial effects, thus displaying excellent photocatalytic NO removal activity (68.08%). The formation of TiO2 is directly confirmed by characterizations such as X-ray diffraction (XRD), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS). Meanwhile, UV–vis, photoluminescence, and photoelectrochemical analysis indicate that TiO2 formation effectively improves the optical properties. Moreover, the strong electron interaction and electron transport direction between NM-125 and TiO2 are investigated by density functional theoretical (DFT) calculation. Finally, combined with the results of electron spin resonance (ESR) and in-situ FT-IR test, the intermediate processes of NO adsorption and photocatalytic oxidation reaction are discussed in depth, where the production of reactive oxygen species (ROS) under light is the key factor in the successful degradation of NO. Compared with NM-125 which can only produce •OH through photogenerated electrons since the lower valence band position, NMT-2 can directly produce •OH through photogenerated holes, thereby relieving the pressure on photogenerated electrons and producing more ROS. This study will provide reasonable guidance for the modification of NM-125 for photocatalytic removal of ppb-level NO.
Solar-driven H2O2 production and emerging organic pollutants (EOPs) elimination are of great significance from the perspective of environmental sustainability. The efficiency of the photocatalytic reaction system is the key challenge to be addressed. In this work, the strategy of constructing surface ionic local polarization centers to enhance the exciton dissociation of the polymeric photocatalytic is demonstrated. Selected bipyridinium cation (TMAP) is complexed on a K+-incorporated carbon nitride (CNK) framework, and the combination of local polarization centers both on the surface (bipyridinium cation) and bulk (K+ cation) contributes to a superior photocatalytic H2O2 production performance, affording a remarkable H2O2 generation rate of 46.8 µmol h−1 mg−1 and a high apparent quantum yield (AQY) value of 77.5% under irradiation of 405 nm photons. As substantiated experimentally by steady state/transient spectroscopy techniques, the surface local polarization centers increase the population of the long-lived trapped electrons, and thereby promote the interfacial charge transfer process for chemical conversion reaction. The strategy is potentially applicable to the design of a wide range of efficient solar-to-chemical conversion systems.
Photothermal hydrogels with excellent photo responsive and thermal conversion ability had attract a great deal of attention from researchers to explore their biological applications. This review aimed to provide a comprehensive overview of photothermal hydrogels, focusing on their design principles, various functions, and biological applications. Firstly, several classifications of photothermal hydrogels were given according to different photothermal agents (metal, metal sulfide/oxide, MXene, carbon-based, dyes, black phosphorus, and polymer) utilized in hydrogel construction. The photothermal conversion mechanism and hydrogel fabrication were also discussed in detail. Then, the relationship between their photothermal conversion property and functions, together with some indispensable property such as biocompatibility, adhesion, mechanical properties, and self-healing properties was fully introduced. Furthermore, the applications of photothermal hydrogels in the biomedical (i.e., wound healing, antibacterial treatments, controlled drug release, bone repair, and tumor treatment) was summarized. Finally, the future opportunities and challenges of photothermal hydrogels were proposed. We believe that this review could provide a new horizon for further preparation of photothermal hydrogels, and could promote their applications in wider fields.
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