Ferroptosis regulates cell death through reactive oxygen species (ROS)‐associated lipid peroxide accumulation, which is expected to affect the structure and polarity of lipid droplets (LDs), but with ...no clear evidence. Herein, we report the first example of an LD/nucleus dual‐targeted ratiometric fluorescent probe, CQPP, for monitoring polarity changes in the cellular microenvironment. Due to the donor–acceptor structure of CQPP, it offers ratiometric fluorescence emission and fluorescence lifetime signals that reflect polarity variations. Using nucleus imaging as a reference, CQPP was applied to report the increase in LD polarity and the homogenization of polarity between LDs and cytoplasm in the ferroptosis model. This LD/nucleus dual‐targeted fluorescent probe shows the great potential of using fluorescence imaging to study ferroptosis and ferroptosis‐related diseases.
The first lipid droplet (LD)/nucleus dual‐targeted ratiometric fluorescence probe, CQPP, for monitoring polarity change was developed. CQPP offers ratiometric fluorescence and fluorescence lifetime imaging of LD polarity variations. Using nucleus imaging as a reference, CQPP was applied to report the increase in LD polarity and the homogenization of polarity between LDs and cytoplasm in the ferroptosis model.
The genetic code is degenerate, and most amino acids are encoded by two to six synonymous codons. Codon usage bias, the preference for certain synonymous codons, is a universal feature of all genomes ...examined. Synonymous codon mutations were previously thought to be silent; however, a growing body evidence now shows that codon usage regulates protein structure and gene expression through effects on co-translational protein folding, translation efficiency and accuracy, mRNA stability, and transcription. Codon usage regulates the speed of translation elongation, resulting in non-uniform ribosome decoding rates on mRNAs during translation that is adapted to co-translational protein folding process. Biochemical and genetic evidence demonstrate that codon usage plays an important role in regulating protein folding and function in both prokaryotic and eukaryotic organisms. Certain protein structural types are more sensitive than others to the effects of codon usage on protein folding, and predicted intrinsically disordered domains are more prone to misfolding caused by codon usage changes than other domain types. Bioinformatic analyses revealed that gene codon usage correlates with different protein structures in diverse organisms, indicating the existence of a codon usage code for co-translational protein folding. This review focuses on recent literature on the role and mechanism of codon usage in regulating translation kinetics and co-translational protein folding. Video abstract.
DNA G-quadruplexes are not only attractive drug targets for cancer therapeutics, but also have important applications in supramolecular assembly. Here, we report a platinum(II)-based tripod ...(Pt-tripod) specifically binds the biological relevant hybrid-1 human telomeric G-quadruplex (Tel26), and strongly inhibits telomerase activity. Further investigations illustrate Pt-tripod induces the formation of monomeric and multimeric Pt-tripod‒Tel26 complex structures in solution. We solve the 1:1 and the unique dimeric 4:2 Pt-tripod-Tel26 complex structures by NMR. The structures indicate preferential binding of Pt-tripod to the 5'-end of Tel26 at a low Pt-tripod/Tel26 ratio of 0-1.0. After adding more Pt-tripod, the Pt-tripod binds the 3'-end of Tel26, unexpectedly inducing a unique dimeric 4:2 structure interlocked by an A:A non-canonical pair at the 3'-end. Our structures provide a structural basis for understanding the dynamic binding of small molecules with G-quadruplex and DNA damage mechanisms, and insights into the recognition and assembly of higher-order G-quadruplexes.
Activation of the cyclic GMP‐AMP synthase‐stimulator of the interferon gene (cGAS‐STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way ...to stimulate the anticancer immune responses. Herein, two PtII complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS‐STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activate the cGAS‐STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS‐STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.
The first small molecule that can activate cGAS‐STING in a photocontrollable way is reported. Upon irradiation, Pt1 and Pt2 can damage mitochondrial DNA, the nuclear envelope and nuclear DNA sequentially, which effectively releases DNA into cytoplasm to activate the cGAS‐STING pathway both in vitro and in vivo.
G‐quadruplex DNA show structural polymorphism, leading to challenges in the use of selective recognition probes for the accurate detection of G‐quadruplexes in vivo. Herein, we present a tripodal ...cationic fluorescent probe, NBTE, which showed distinguishable fluorescence lifetime responses between G‐quadruplexes and other DNA topologies, and fluorescence quantum yield (Φf) enhancement upon G‐quadruplex binding. We determined two NBTE‐G‐quadruplex complex structures with high Φf values by NMR spectroscopy. The structures indicated NBTE interacted with G‐quadruplexes using three arms through π–π stacking, differing from that with duplex DNA using two arms, which rationalized the higher Φf values and lifetime response of NBTE upon G‐quadruplex binding. Based on photon counts of FLIM, we detected the percentage of G‐quadruplex DNA in live cells with NBTE and found G‐quadruplex DNA content in cancer cells is 4‐fold that in normal cells, suggesting the potential applications of this probe in cancer cell detection.
G4 imaging: A tripodal cationic fluorescence probe, NBTE, was used for the visualization (based on fluorescence lifetime) and quantification (based on photon counts) of G‐quadruplex DNA in live cells by fluorescence lifetime imaging microscopy (FLIM). Structural studies provided a structural basis for the DNA‐topology‐based fluorescence response of NBTE.
The nucleus is considered the ideal target for anti‐tumor therapy because DNA and some enzymes in the nucleus are the main causes of cell canceration and malignant proliferation. However, nuclear ...target drugs with good biosafety and high efficiency in cancer treatment are rare. Herein, a nuclear‐targeted material MeTPAE with aggregation‐induced emission (AIE) characteristics was developed based on a triphenylamine structure skeleton. MeTPAE can not only interact with histone deacetylases (HDACs) to inhibit cell proliferation but also damage telomere and nucleic acids precisely through photodynamic treatment (PDT). The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent PDT anti‐tumor activity, which offered new opportunities for the effective treatment of malignant tumors.
A nuclear‐targeted material MeTPAE with AIE characteristics was developed. MeTPAE can not only interact with HDACs to inhibit cell proliferation, but also damage telomere and nucleic acids precisely through photodynamic treatment. The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent photodynamic therapy (PDT) anti‐tumor activity, which offered new opportunities for the effective treatment of malignant tumors.
Developing noble‐metal‐free electrocatalysts is important to industrially viable ammonia synthesis through the nitrogen reduction reaction (NRR). However, the present transition‐metal ...electrocatalysts still suffer from low activity and Faradaic efficiency due to poor interfacial reaction kinetics. Herein, an interface‐engineered heterojunction, composed of CoS nanosheets anchored on a TiO2 nanofibrous membrane, is developed. The TiO2 nanofibrous membrane can uniformly confine the CoS nanosheets against agglomeration, and contribute substantially to the NRR performance. The intimate coupling between CoS and TiO2 enables easy charge transfer, resulting in fast reaction kinetics at the heterointerface. The conductivity and structural integrity of the heterojunction are further enhanced by carbon nanoplating. The resulting C@CoS@TiO2 electrocatalyst achieves a high ammonia yield (8.09×10−10 mol s−1 cm−2) and Faradaic efficiency (28.6 %), as well as long‐term durability.
Junction box: An interface‐engineered heterojunction, composed of carbon‐nanoplated CoS@TiO2 nanofibrous membrane, is developed for the nitrogen reduction reaction. The resulting C@CoS@electrocatalyst achieves strikingly high ammonia yield (8.09×10−10 mol s−1 cm−2) and Faradaic efficiency (28.6 %), as well as long‐term durability.
G‐quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4‐mediated immune response remains unclear. We designed a novel class of ...G4‐binding organic‐platinum hybrids, L1‐cispt and L1‐transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L1‐transpt‐MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding‐guided dynamic balance, accompanied by the destruction of the A5‐T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L1‐cispt‐ and L1‐transpt‐mediated genomic dysfunction could activate the retinoic acid‐induced gene I (RIG‐I) pathway and induce immunogenic cell death (ICD). The use of L1‐cispt/L1‐transpt‐treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4‐trageting drug design and their potential in immunotherapy.
A novel class of G4‐targeting organic‐platinum hybrids, L1‐cispt and L1‐transpt, designed to covalently bind to the G4 binding site, could activate the retinoic acid‐induced gene I (RIG‐I) pathway, induce immunogenic cell death (ICD) and stimulate potent immunotherapy in vivo. This study highlights the importance of the rational combination of specific spatial recognition and covalent binding in G4‐targeting drug design.
ABSTRACT Magnetic reconnection is thought to be the driver for many explosive phenomena in the universe. The energy release and particle acceleration during reconnection have been proposed as a ...mechanism for producing high-energy emissions and cosmic rays. We carry out two- and three-dimensional (3D) kinetic simulations to investigate relativistic magnetic reconnection and the associated particle acceleration. The simulations focus on electron-positron plasmas starting with a magnetically dominated, force-free current sheet ( ). For this limit, we demonstrate that relativistic reconnection is highly efficient at accelerating particles through a first-order Fermi process accomplished by the curvature drift of particles along the electric field induced by the relativistic flows. This mechanism gives rise to the formation of hard power-law spectra and approaches p = 1 for sufficiently large and system size. Eventually most of the available magnetic free energy is converted into nonthermal particle kinetic energy. An analytic model is presented to explain the key results and predict a general condition for the formation of power-law distributions. The development of reconnection in these regimes leads to relativistic inflow and outflow speeds and enhanced reconnection rates relative to nonrelativistic regimes. In the 3D simulation, the interplay between secondary kink and tearing instabilities leads to strong magnetic turbulence, but does not significantly change the energy conversion, reconnection rate, or particle acceleration. This study suggests that relativistic reconnection sites are strong sources of nonthermal particles, which may have important implications for a variety of high-energy astrophysical problems.
It is of great significance to track the platinum drugs in real time with super‐resolution to elucidate their mechanism of action, such as their behavior and distribution in live cells. Such ...information is required for further drug development. However, it is always challenging to design platinum complexes suitable for such research. Herein, we design a luminescent building block (L) for metal complexes and a dinuclear platinum complex (Pt2L) for super‐resolution imaging. Because of its super‐large Stokes shift and excellent photophysical properties, Pt2L is capable of serving as an ideal candidate for super‐resolution imaging with extremely low luminescence background and high photobleaching resistance. Moreover, upon light stimulation, a matter flux of Pt2L escaping from autolysosomes to nucleus was observed, which represents a new transportation path. Utilizing the photoactivated escape properties, we can regulate the nuclear accessibility of Pt2L form autolysosomes with photo‐selectivity, which provides a new way to improve the targeting of platinum drugs.
A multiple‐color platinum complex (Pt2L) with super‐large Stokes shift was designed for super‐resolution imaging, showing an extremely low luminescence background and high photobleaching resistance. Moreover, upon light stimulation, a matter flux of Pt2L escaping from autolysosomes to the nucleus is detected, which represents a new transportation path.
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