Latest ArticlesImaging detection of interlinked dual proteases is imperative for precise tumor imaging, which remains challenging due to limited modification position of specific substrate and possible steric hindrance. Herein, we have developed a unimolecular chemiluminescent probe (LGP-CL) tandemly activated by two proteases interlinked with liver cancer to achieve precise tumor imaging. Probe LGP-CL consists of a phenoxy-dioxetane scaffold caged by a tripeptide substrate (LGP, leucine-glycine-proline) as the sensing layer, which can be cleaved sequentially by aminopeptidase N (APN) and dipeptidyl peptidase Ⅳ (DPPIV) to turn on a strong chemiluminescent signal, and silenced by specific inhibitor of each enzyme, which accounts for an integrated logic gate (AND, OR and INHIBIT). The successful cleavage of dual proteases on the metabolic site depends on the proper structure of the tripeptide substrate, as confirmed by two probes design. Probe LGP-CL (LGP as the substrate) enables the excellent "dual-lock-dual-key" fit with a 382-fold enhancement of chemiluminescent emission while no obvious signal is observed by using GPL-CL (GPL as the substrate). By virtue of its rapid response (several minutes), high sensitivity and good cell viability, probe LGP-CL has been utilized to evaluate upregulated levels of proteases in vitro and in living systems, especially to distinguish liver tumor cells (HepG2) from others (LO2, MCF-7, MCF-10a and RAW264.7). Overall, the newly developed CL probe may facilitate rapid investigation into the role played by proteases in liver diseases, enabling timely selection appropriate treatment. Therefore, our work not only sheds light on the rational design of optical probes for dual protease imaging, but provides a promising tool for clinical diagnosis and even drug discovery.
Planktonic bacteria adhere and subsequently form biofilms on implantable medical devices can cause severe infections that have become the major types of hospital-acquired infections. Traditional coatings for the implants are frequently lack of long-term antifouling and bactericidal activities. It is still a big challenge to simultaneously improve the antifouling and bactericidal activities of the coatings. Herein, we report that mixed-charge glycopolypeptide coatings are of long-term antibacterial activities to efficiently inhibit the biofilm growth. The glycosylation of mixed-charge polypeptides has led to a significant improvement of both antifouling and bactericidal activities. The cooperative effect of the saccharide residues and mixed-charge residues improved the resistance of the polypeptide coatings against protein adsorption. The saccharide and L-glutamic acid (E) residues collectively enhanced the bacterial membrane-disruption of cationic L-lysine (K) residues, leading to potent bactericidal activity. Meanwhile, the glycopolypeptide coatings showed superior biocompatibility, long-term antibiofilm and anti-infection properties in two types of mouse subcutaneous infection models and one type of mouse urinary tract infection model. This work provides a new strategy to achieve antibacterial coatings with long-term activities for preventing implantable medical device associated infections.
Ultrasensitive detection of nucleic acids is of great significance for precision medicine. Digital polymerase chain reaction (dPCR) is the most sensitive method but requires sophisticated and expensive instruments and a long reaction time. Digital PCR-free technologies, which mean the digital assay not relying on thermal cycling to amplify the signal for quantitative detection of nucleic acids at the single-molecule level, include the digital isothermal amplification techniques (dIATs) and the digital clustered regularly interspaced short palindromic repeats (CRISPR) technologies. They combine the advantages of dPCR and IATs, which could be fast and simple, enabling absolute quantification of nucleic acids at a single-molecule level with minimum instrument, representing the next-generation molecular diagnostic technology. Herein, we systematically summarized the strategies and applications of various dIATs, including the digital loop-mediated isothermal amplification (dLAMP), the digital recombinase polymerase amplification (dRPA), the digital rolling circle amplification (dRCA), the digital nucleic acid sequence-based amplification (dNASBA) and the digital multiple displacement amplification (dMDA), and evaluated the pros and cons of each method. The emerging digital CRISPR technologies, including the detection mechanism of CRISPR and the various strategies for signal amplification, are also introduced comprehensively in this review. The current challenges as well as the future perspectives of the digital PCR-free technology were discussed.
The extracellular vesicles show great potential as a noninvasive biomarker for the early detection of cancer. Hence, there is an urgent requirement to create biosensors that are time-saving, simple, and easily scalable in order to accomplish rapid, sensitive, and quantitative detection of extracellular vesicles. In this study, we present a self-propelled DNA walker powered by endonuclease Nt.BbvCI, which enables the development of a "signal on" sensing platform for the rapid and highly sensitive detection of extracellular vesicles. The DNA motor employed tracks made of streptavidin magnetic beads, which consisted of substrate strands labeled with fluorescein and motor strands locked by aptamers. The aptamer recognition of the target protein on extracellular vesicles unlocked the motor strand, initiating the DNA motor process. After replacing the optimal buffer solution containing the endonuclease Nt.BbvCI, the motor strands autonomously moved along the streptavidin magnetic beads track, continuously releasing fluorescent molecules and producing detectable fluorescence signals. Under optimal conditions, the detection range was from 2×104 particles/mL to 2×109 particles/mL, with a detection limit of 2.9×103 particles/mL, demonstrating excellent selectivity. This method has demonstrated good selectivity in different tumor-derived extracellular vesicles and performs well in complex biological samples. The ability to effectively analyze surface proteins of extracellular vesicles in a short period of time gives our DNA walker a tremendous potential for developing simple and cost-effective clinical diagnostic devices.
The interface modulation significantly affects the photocatalytic performances of supported metal phthalocyanines (MPc)-based systems. Herein, ZnPc was loaded on nanosized Au-modified TiO2 nanosheets (Au-T) to obtain wide-spectrum ZnPc/Au-T photocatalysts. Compared with large Au NP (8 nm)-mediated ZnPc/Au-T photocatalyst, ultrasmall Au NP (3 nm)-mediated one shows advantageous photoactivity, achieving 3- and 10-fold CO2 conversion rates compared with reference ZnPc/T and pristine TiO2 nanosheets, respectively. Employing monochromatic beam-assisted surface photovoltage and photocurrent action, etc., the introduction of ultrasmall Au NPs more effectively facilitates intrinsic interfacial charge transfer. Moreover, ZnPc molecules are found more dispersed with the existence of small Au NPs hence exposing abundant Zn2+sites as the catalytic center for CO2 reduction. This work provides a feasible design strategy and renewed recognition for supported MPc-based photocatalyst systems.
Gold-catalyzed amination reactions based on azides via α-imino gold carbene intermediates have attracted extensive attention in the past decades because this methodology leads to the facile and efficient construction of synthetically useful N-containing molecules, especially valuable N-heterocycles. However, successful examples of intermolecular generation of α-imino gold carbenes by using azides as amination reagents are rarely explored probably due to the weak nucleophilicity of azides. Herein, we disclose an efficient gold-catalyzed intermolecular aminative cyclopropanation of ynamides with the allyl azides, enabling flexible synthesis of a wide range of valuable 3-azabicyclo[3.1.0]hex-2-ene derivatives in good to excellent yields with excellent diastereoselectivities. Importantly, this protocol represents the first use of allyl azide as an efficient amination reagent in gold-catalyzed alkyne amination reactions.
The first total synthesis of (+)-taberdicatine B and (+)-tabernabovine B has been accomplished in 10 steps with 26.9% overall yield and 15 steps with 7.3% overall yield, respectively. The prominent features of this efficient synthetic strategy include the following: (1) (+)-Taberdicatine B and (+)-tabernabovine B were accessed from common advanced intermediates by varying the substituents; (2) A one-pot asymmetric bromocyclization/hydrolysis was explored to assemble HPI skeleton; (3) Dieckmann condensation to form β-keto ester for the assembly of seven-membered ring; (4) An ester reduction/amide semireduction/cyclization sequence was applied to form the cage-like framework.
Rare–earth supramolecular compounds, such as lanthanide organic polyhedrons (LOPs), are of particular interest due to their many possible applications in various fields. Here we report the first syntheses of Ln4(L•+)4–type (Ln, lanthanides; L•+, radical ligand) radical–bridged lanthanide organic tetrahedrons by self–assembly of face–capping triphenylamine (TPA)–cored radical ligand with different lanthanide ions. Remarkable coordination enhanced radical stability has been observed, with half–life times (t1/2) for L1•+, La4(L1•+)4, Eu4(L1•+)4, Gd4(L1•+)4, Tb4(L1•+)4 and Lu4(L1•+)4 estimated to be 53 min, 482 min, 624 min, 1248 min, 822 min and 347 min, respectively. The TPA radical in Ln4(L1•+)4 containing paramagnetic Ln ions (Ln = EuⅢ, GdⅢ and TbⅢ) is observed to be more stable than that in Ln4(L1•+)4 (Ln = LaⅢ and LuⅢ) constructed by diamagnetic Ln ions. This difference in radical stability is possibly due to the magnetic interactions between paramagnetic LnⅢ ions and L1•+ ligands, as confirmed by electron paramagnetic resonance (EPR) in La4(L)4 (L = L1 and L1•+) and Tb4(L)4 (L = L1 and L1•+), and magnetic susceptibility measurements in Tb4(L)4 (L = L1 and L1•+). Our study reveals the coordination of radical ligands with lanthanide ions can improve the radical stability, which is crucial for their applications.
The preparation of immobilized enzyme with excellent performance is one of the difficulties that restrict the application of enzyme catalysis technology. Here, Candida rugosa lipase (CRL) was firstly adsorbed on the surface of magnetic zeolitic imidazolate framework-8 (ZIF-8) nanospheres, which was further encapsulated with a mesoporous SiO2 nano-membrane formed by tetraethyl orthosilicate (TEOS) polycondensation. Consequently, lipase could be firmly immobilized on carrier surface by physical binding rather than chemical binding, which did not damage the active conformation of enzyme. There were mesopores on the silica nano-membrane, which could improve the accessibility of enzyme and its apparent catalytic activity. Moreover, silica membrane encapsulation could also improve the stability of enzyme, suggesting an effective enzyme immobilization strategy. It showed that TEOS amount and the encapsulation time had significant effects on the thickness of silica membrane and the enzyme activity. The analysis in enzyme activity and protein secondary structure showed that lipase encapsulated in silica membrane retained the active conformation to the greatest extent. Compared with the adsorbed lipase, the encapsulated lipase increased its thermostability by 3 times and resistance to chemical denaturants by 7 times. The relative enzyme activity remained around 80% after 8 repetitions, while the adsorbed lipase only remained at 7.3%.
Photodynamic therapy (PDT) presents a promising avenue in cancer treatment. Erlotinib, an FDA-approved anticancer drug targeting epidermal growth factor receptor (EGFR), has shown effectiveness in normalizing tumor vasculature across various tumors, thereby promoting tumor oxygenation and facilitating PDT. In this work, erlotinib was conjugated with a near-infrared (NIR) photosensitizer, benzo[a]phenoselenazinium, yielding three EGFR-targeted PDT agents (NBSe-nC-Er). These newly synthesized photosensitizers demonstrate specificity in binding to EGFR, thereby enhancing their accumulation in cancer cells and tumors, and consequently improving the efficiency of both PDT and chemotherapy. Additionally, the NIR fluorescence emitted by the photosensitizer allows for imaging-guided therapy, offering a non-invasive means of monitoring treatment progress. The distinctive properties of the three-in-one photosensitizer render it an ideal candidate for precise tumor treatment, overcoming the limitations of conventional therapies.
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