Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 µM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

An improved ligand-assisted reprecipitation method to synthesize aqueous-phase CsPbBr3 perovskite nanocrystals and investigate their electrochemiluminescence behavior.

We propose a novel ligand-assisted reprecipitation method to synthesize aqueous-phase CsPbBr3 nanocrystals, the fluorescence intensity of which remained at 51% after 120 h. As a multifunctional additive, cesium trifluoroacetate (Cs-TFA) can improve the surface adsorption energy and induce nanocrystals to show significant anodic electrochemiluminescence (ECL) and stable cathodic ECL performances.

Multi-Walled Carbon Nanotube Array Modified Electrode with 3D Sensing Interface as Electrochemical DNA Biosensor for Multidrug-Resistant Gene Detection.

Drug resistance in cancer is associated with overexpression of the multidrug resistance (MDR1) gene, leading to the failure of cancer chemotherapy treatment. Therefore, the establishment of an effective method for the detection of the MDR1 gene is extremely crucial in cancer clinical therapy. Here, we report a novel DNA biosensor based on an aligned multi-walled carbon nanotube (MWCNT) array modified electrode with 3D nanostructure for the determination of the MDR1 gene. The microstructure of the modified electrode was observed by an atomic force microscope (AFM), which demonstrated that the electrode interface was arranged in orderly needle-shaped protrusion arrays. The electrochemical properties of the biosensor were characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Chronocoulometry (CC) was used for the quantitative detection of the MDR1 gene. Taking advantage of the good conductivity and large electrode area of the MWCNT arrays, this electrochemical DNA sensor achieved a dynamic range from 1.0 × 10-12 M to 1.0 × 10-8 M with a minimal detection limit of 6.4 × 10-13 M. In addition, this proposed DNA biosensor exhibited high sensitivity, selectivity, and stability, which may be useful for the trace analysis of the MDR1 gene in complex samples.

Energy Level Engineering in Gold Nanoclusters for Exceptionally Bright NIR Electrochemiluminescence at a Low Trigger Potential.

Electrochemiluminescence (ECL) is a widely used light output mechanism from electrochemical excitation. Understanding the intrinsic essence for ideal ECL generation remains a fundamental challenge. Here, based on the molecular orbital theory, we reported an energy level engineering strategy to regulate the ECL performance by using ligand-protected gold nanoclusters (AuNCs) as luminophores and N,N-diisopropylethylamine (DIPEA) as a coreactant. The energy level matching between the AuNCs and DIPEA effectively promoted their electron transfer reactions, thus improving the excitation efficiency and reducing the trigger potential. Simultaneously, the narrow band gap of the AuNCs further enabled enhanced emission efficiency. Using the energy level engineering theory developed here, a dual-enhanced strategy was proposed, and ß-CD-AuNCs were designed to further verify this mechanism. The ß-CD-AuNCs/DIPEA system resulted in highly stable near-infrared ECL with an unprecedented ECL efficiency (145-fold higher than that of the classic Ru(bpy)32+/tetra-n-butylammonium perchlorate system) and a low trigger potential of 0.48 V. A visual NIR-ECL based on this ECL system was successfully realized by an infrared camera. This work provides an original mechanistic understanding for designing efficient ECL systems, which promises to be a harbinger for broad applicability of this strategy for other ECL systems and ECL sensing platforms.

Promoting the healing of methicillin-resistant Staphylococcus aureus-infected wound by a multi-target antimicrobial AIEgen of 6-Aza-2-thiothymine-decorated gold nanoclusters.

The use of conventional antibiotic therapies is in question owing to the emergence of drug-resistant pathogenic bacteria. Therefore, novel, highly efficient antibacterial agents to effectively overcome resistant bacteria are urgently needed. Accordingly, in this work, we described a novel class luminogen of 6-Aza-2-thiothymine-decorated gold nanoclusters (ATT-AuNCs) with aggregation-induced emission property that possessed potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). Scanning electron microscopy was performed to investigate the interactions between ATT-AuNCs and MRSA. In addition, ATT-AuNCs exhibited excellent ROS generation efficiency and could effectively ablate MRSA via their internalization to the cells. Finally, tandem mass tag-labeling proteome analysis was carried out to investigate the differential expression proteins in MRSA strains. The results suggested that ATT-AuNCs killed MRSA cells through altering the expression of multiple target proteins involved in DNA replication, aminoacyl-tRNA synthesis, peptidoglycan and arginine biosynthesis metabolism. Parallel reaction monitoring technique was further used for the validation of these proteome results. ATT-AuNCs could also be served as a wound-healing agent and accelerate the healing process. Overall, we proposed ATT-AuNCs could serve as a robust antimicrobial aggregation-induced emission luminogen (AIEgen) that shows the ability to alter the activities of multiple targets for the elimination of drug-resistant bacteria.

Multi-excitation wavelength of gold nanocluster-based fluorescence sensor array for sulfonamides discrimination.

Sulfonamides (SAs) are widely used in many fields because of their advantages, including low price, wide antibacterial spectrum, and high stability. However, their accumulation in the human body leads to a variety of serious diseases. Therefore, it is necessary to design a convenient, effective, and sensitive method to detect SAs. Moreover, the fluorescence excitation spectrum has rich information characteristics, especially for the interaction between fluorophore and quencher via various mechanisms. However, the excitation wavelength-guided sensor array construction does not draw proper attention. To address these issues, we used BSA-AuNCs as a single probe to construct a sensor array for the detection of five SAs. The selected SAs showed different quenching effects on the fluorescence intensities of BSA-AuNCs. The changes in the fluorescence intensity at different excitation wavelengths (λ = 230, 250, and 280 nm) have been applied to construct our sensor array and address the distinguishability between the selected SAs. With helping of pattern recognition methods, five different SAs have been identified at three different concentrations. Additionally, qualitative analysis at different moral ratios and quantitative analysis at nanogram concentrations have been considered. Moreover, the proposed sensor array was successfully used to distinguish between different SAs in commercial milk with an accuracy of 100 %. This study provides a simple and powerful approach to SAs detection. Also, it shows a broad application prospect in the field of food and drug monitoring.

Feature Selection Assists BLSTM for the Ultrasensitive Detection of Bioflavonoids in Different Biological Matrices Based on the 3D Fluorescence Spectra of Gold Nanoclusters.

Rapid and on-site qualitative and quantitative analysis of small molecules (including bioflavonoids) in biofluids are of great importance in biomedical applications. Herein, we have developed two deep learning models based on the 3D fluorescence spectra of gold nanoclusters as a single probe for rapid qualitative and quantitative analysis of eight bioflavonoids in serum. The results proved the efficiency and stability of the random forest-bidirectional long short-term memory (RF-BLSTM) model, which was used only with the most important features after deleting the unimportant features that might hinder the performance of the model in identifying the selected bioflavonoids in serum at very low concentrations. The optimized model achieves excellent overall accuracy (98-100%) in the qualitative analysis of the selected bioflavonoids. Next, the optimized model was transferred to quantify the selected bioflavonoids in serum at nanoscale concentrations. The transferred model achieved excellent accuracy, and the overall determination coefficient (R2) value range was 99-100%. Furthermore, the optimized model achieved excellent accuracies in other applications, including multiplex detection in serum and model applicability in urine. Also, LOD in serum at nanoscale concentration was considered. Therefore, this approach opens the window for qualitative and quantitative analysis of small molecules in biofluids at nanoscale concentrations, which may help in the rapid inclusion of sensor arrays in biomedical and other applications.

Gold Nanocluster Probe-Based Electron-Transfer-Mediated Electrochemiluminescence Sensing Strategy for an Ultrasensitive Copper Ion Detection.

Exploration of a novel and efficient sensing mechanism of Au nanocluster (AuNC)-based electrochemiluminescence (ECL) sensors is still a great challenge and opportunity for further applications. Herein, we proposed that the electron transfer (ET) could be used as a novel sensing regulation factor for the construction of an ECL-sensing platform based on the AuNC probe. As a proof-of-concept, the ECL quenching effect and mechanism of Cu2+ on pre-oxidation-treated l-methionine-capped AuNCs (OM-AuNCs) was investigated in detail. The results revealed that after the electrochemical excitation of the AuNC probe, the electron is transferred from the highest occupied molecular orbital (HOMO) of Met-Cu2+ to that of the OM-AuNCs, along with the ET from lowest-unoccupied molecular orbital (LUMO) of the OM-AuNCs back to the HOMO of Met-Cu2+, leading to the ECL quenching of OM-AuNCs. Since the ECL intensity of OM-AuNCs is sensitively affected by the ET process, a preferable linear dependence was obtained in the concentration range from 1.0 × 10-18 to 1.0 × 10-14 M with high selectivity. More importantly, a record low detection limit (LOD, 2.3 × 10-20 M) at the single copper ion level has been realized without any other amplification technique. Furthermore, the actual sample detection for Cu2+ exhibited satisfactory results. Therefore, this study enriches an ET-mediated ECL application and promotes a more rational design of ECL sensors.

Machine learning-based sensor array: full and reduced fluorescence data for versatile analyte detection based on gold nanocluster as a single probe.

Different acquisition data approaches have been used to fetch the fluorescence spectra. However, the comparison between them is rare. Also, the extendability of a sensor array, which can work with heavy metal ions and other types of analytes, is scarce. In this study, we used first- and second-order fluorescent data generated by 6-Aza-2-thiothymine-gold nanocluster (ATT-AuNCs) as a single probe along with machine learning to distinguish between a group of heavy metal ions. Moreover, the dimensionality reduction was carried out for the different acquisition data approaches. In our case, the accuracy of different machine learning algorithms using first-order data outperforms the second-order data before and after the dimensionality reduction. For proving the extendibility of this approach, four anions were used as an example. As expected, the same finding has been found. Furthermore, random forest (RF) showed more stable and accurate results than other models. Also, linear discriminant analysis (LDA) gave acceptable accuracy in the analysis of the high-dimensionality data. Accordingly, using LDA in high-dimensionality data (the first- and second-order data) analysis was highlighted for discrimination between the selected heavy metal ions in different concentrations and in different molar ratios, as well as in real samples. Also, the same method was applied for the anion's discrimination, and LDA gave an excellent separation ability. Moreover, LDA was able to differentiate between all the selected analytes with excellent separation ability. Additionally, the quantitative detection was considered using a wide concentration range of Cd2+, and the LOD was 60.40 nM. Therefore, we believe that our approach opens new avenues for linking analytical chemistry, especially sensor array chemistry, with machine learning.

Carboxylated chitosan enabled platinum nanozyme with improved stability and ascorbate oxidase-like activity for a fluorometric acid phosphatase sensor.

Chitosan modification has attracted considerable interest in the nanozyme field last decade. As a chitosan derivative, carboxylated chitosan (CC) has been less explored. Herein, PtNPs with an average size of approximately 3.3 nm and zeta potential of -44.8 ± 0.3 mV (n = 3) have been prepared by using CC as the surface modification (CC-PtNPs). We have carried out an in-depth investigation of CC-PtNPs, including the characterization, colloidal stability, and ascorbate oxidase-like activity. Due to the contribution of carboxylated chitosan, CC-PtNPs present improved colloidal stability and ascorbate oxidase-like activity compared to chitosan-modified Pt nanozyme. Inspired by these results, a fluorometric acid phosphatase sensor was proposed based on the improved performance of CC-PtNPs. This sensor exhibits excellent sensitivity and selectivity towards acid phosphatase in the linear range of 0.25-18 U/L with a low limit of detection (1.31 × 10-3 U/L). The concentration of acid phosphatase in human semen samples has been successfully measured.

Co-Reactant-Mediated Low-Potential Anodic Electrochemiluminescence Platform and Its Immunosensing Application.

Screening high-performance anodic electrochemiluminescence (ECL) systems with low triggering potential is a promising way to broaden their applications. In addition to electrochemiluminophore, co-reactant also plays an important role in the ECL process, since the oxidation of co-reactants is one of the most important steps in the anodic ECL process. Herein, a novel co-reactant-mediated high-performance low-potential Au nanocluster (AuNC)-based ECL system has been successfully developed. Benefiting from the isopropyl substitution and hydroxyl addition to the triethylamine (TEA), the BSA-AuNC/2-(diisopropylamino)ethanol (DIPEA-OH) ECL system achieved higher energy efficiency at a lower potential of 0.75 V. In addition, compared with the BSA-AuNC/TEA system, the ECL intensity and quantum yield (ΦECL) with DIPEA-OH as a co-reactant increased 22.34-fold and 13-fold (as high as 68.17%), respectively. Based on the low potential, high ΦECL of the AuNC/DIPEA-OH ECL system, a sandwich-type immunosensor has been constructed for a highly selective SARS-CoV-2 N protein assay. In the absence of any complex signal amplification strategies, the ECL immunosensor for the SARS-CoV-2 N protein detection showed a linear range of 0.001-100 ng/mL and a detection limit of 0.35 pg/mL. Moreover, the ECL platform had good reproducibility and stability and exhibited acceptable detection performance in the detection of actual serum samples. This work established a framework for in-depth design and study of anode ECL co-reactants for AuNCs and other luminophores, and expanded the potential application of ECL sensors in the clinical diagnosis of COVID-19.

Facile high-quantum-yield sulfur-quantum-dot-based photoluminescent probe for nifedipine detection.

Monitoring of dihydropyridine drugs, such as nifedipine (NIF), has attracted considerable attention owing to the side effects arising from the consumption of such drugs. Herein, a highly sensitive and facile fluorescence-sensing platform based on a high-quantum-yield sulfur quantum dot (SQDs) probe for NIF detection is proposed. Based on the principle of the inner filter effect, the rapid detection of NIF with high sensitivity is successfully realized on the basis of the change in the fluorescence signal due to the quenching effect of NIF on SQDs. The results show a good linear relationship between the NIF concentration and fluorescence intensity within the range of 5-150 µmol/L, with a low detection limit of 1.63 µmol/L (S/N = 3). Moreover, because no surface modification or establishment of any coupling between the receptor and the fluorophore is necessary, this approach provides considerable flexibility and simplicity for the construction of a fluorescence sensor and substantially reduces the detection time. A systematic investigation was conducted to verify the applicability of this method for the analysis of pharmaceutical components in NIF tablets. This study not only promotes the design and development of a fluorescence analysis platform for NIF detection, but also facilitates the fabrication of novel SQD-based fluorescence-sensing systems for the molecular detection of drugs. Proposal for a facile nifedipine assay method based on the inner filter effect of nifedipine to high-quantum-yield sulfur quantum dots, and realizing nifedipine detection in tablets and human urine samples.

Fructose oxidase-like activity of CuO nanoparticles supported by phosphate for a tandem catalysis-based fructose sensor.

A surge of nanozymes with oxidase-like activities is emerging in various fields, whereas nanozymes with the ability to catalyze the oxidation of saccharides have less been explored. Herein, CuO nanoparticles (NPs) with phosphate-supported fructose oxidase-like activity have been reported. Notably, reactive oxygen species (ROS) have been confirmed as the products during the process. By coupling the fructose oxidase-like activity with the peroxidase-like activity of CuO NPs, a tandem catalysis-based fructose sensor can be fabricated. In detail, CuO NPs can catalyze the fructose oxidation under O2 to yield ROS (e.g., H2O2, •OH, and O2·-) and effectively decompose H2O2 into ·OH. After that, terephthalic acid can be oxidized by •OH produced from the tandem catalysis to generate a fluorescent product. This sensor shows a linear range toward fructose (0.625-275 µÐœ) with a low limit of detection (0.5 µÐœ), which can be successfully conducted to detect fructose from real samples. Overall, this work aims to expand the catalytic types of nanozymes and provide a desirable fructose sensor.

Bis-Schiff base linkage-triggered highly bright luminescence of gold nanoclusters in aqueous solution at the single-cluster level.

Metal nanoclusters (NCs) have been developed as a new class of luminescent nanomaterials with potential applications in various fields. However, for most of the metal NCs reported so far, the relatively low photoluminescence quantum yield (QY) in aqueous solution hinders their applications. Here, we describe the utilization of bis-Schiff base linkages to restrict intramolecular motion of surface motifs at the single-cluster level. Based on Au22(SG)18 (SG: glutathione) NCs, an intracluster cross-linking system was constructed with 2,6-pyridinedicarboxaldehyde (PDA), and water-soluble gold NCs with luminescence QY up to 48% were obtained. The proposed approach for achieving high emission efficiency can be extended to other luminescent gold NCs with core-shell structure. Our results also show that the content of surface-bound Au(I)-SG complexes has a significant impact on the PDA-induced luminescence enhancement, and a high ratio of Au(I)-SG will be beneficial to increasing the photoluminescence intensity of gold NCs.

Deep Learning-Based Sensor Array: 3D Fluorescence Spectra of Gold Nanoclusters for Qualitative and Quantitative Analysis of Vitamin B6 Derivatives.

Vitamin B6 derivatives (VB6Ds) are of great importance for all living organisms to complete their physiological processes. However, their excess in the body can cause serious problems. What is more, the qualitative and quantitative analysis of different VB6Ds may present significant challenges due to the high similarity of their chemical structures. Also, the transfer of deep learning model from one task to a similar task needs to be present more in the fluorescence-based biosensor. Therefore, to address these problems, two deep learning models based on the intrinsic fingerprint of 3D fluorescence spectra have been developed to identify five VB6Ds. The accuracy ranges of a deep neural network (DNN) and a convolutional neural network (CNN) were 94.44-97.77% and 97.77-100%, respectively. After that, the developed models were transferred for quantitative analysis of the selected VB6Ds at a broad concentration range (1-100 µM). The determination coefficient (R2) values of the test set for DNN and CNN were 93.28 and 97.01%, respectively, which also represents the outperformance of CNN over DNN. Therefore, our approach opens new avenues for qualitative and quantitative sensing of small molecules, which will enrich fields related to deep learning, analytical chemistry, and especially sensor array chemistry.

6-Aza-2-thio-thymine-gold nanoclusters: an excellent candidate in the photoelectrochemical field.

The high performance of the photoelectrochemical (PEC) properties of AuNCs can be achieved with 6-aza-2-thio-thymine-AuNCs (ATT-AuNCs) as a photoactive material. The ATT-AuNCs yielded a cathodic photocurrent density as high as 88 µA cm-2 with O2 as electron acceptor, which is three orders of magnitude higher than those of other AuNCs in aqueous solutions. Moreover, ATT-AuNCs also show a higher carrier density, shorter Debye length, and smaller depletion layer width than those of reported AuNCs. This work not only reveals the PEC performance and mechanism of ATT-AuNCs, but also establishes a framework for in-depth design and studying the PEC performance of AuNCs.

Antenna effect of pyridoxal phosphate on the fluorescence of mitoxantrone-silicon nanoparticles and its application in alkaline phosphatase assay.

As a kind of sensing and imaging fluorescent probe with the merit of low toxicity, good stability, and environment-friendly, silicon nanoparticles (SiNPs) are currently attracting extensive research. In this work, we obtained mitoxantrone-SiNPs (MXT-SiNPs) with green emission by one-pot synthesis under mild temperature condition. The antenna based on pyridoxal phosphate (PLP) was designed for light-harvesting to enhance the luminescence of MXT-SiNPs and to establish a novel sensing strategy for alkaline phosphatase (ALP). PLP transfers the absorbed photon energy to MXT-SiNPs by forming Schiff base. When PLP is dephosphorized by ALP, the released free hydroxyl group reacts with aldehyde group to form internal hemiacetal, which leads to the failure of Schiff base formation. Based on the relationship between antenna formation ability and PLP hydrolysis degree, the activity of ALP can be measured. A good linear relationship was obtained from 0.2 to 3.0 U/L, with a limit of detection of 0.06 U/L. Furthermore, the sensing platform was successfully used to detect ALP in human serum with recovery of 97.6-106.2%. The rational design of antenna elements for fluorescent nanomaterials can not only provide a new pathway to manipulate the luminescence, but also provide a new direction for fluorescence sensing strategy.

Immunofluorescent-aggregation assay based on anti-Salmonella typhimurium IgG-AuNCs, for rapid detection of Salmonella typhimurium.

Sensitive and rapid detection of pathogenic bacteria plays an important role in avoiding food poisoning. However, the practical application value of conventional assays for detection of foodborne bacteria, are limited by major drawbacks; these include the laboriousness of pure culture preparation, complexity of DNA extraction for polymerase chain reaction, and low sensitivity of enzyme-linked immunosorbent assay. Herein, we designed a non-complex strategy for the sensitive, quantitative, and rapid detection of Salmonella typhimurium with high specificity, using an anti-Salmonella typhimurium IgG-AuNC-based immunofluorescent-aggregation assay. Salmonella typhimurium was agglutinated with fluorescent anti-Salmonella typhimurium IgG-AuNC on a glass slide, and observed using a fluorescence microscope with photoexcitation and photoemission at 560 nm and 620 nm, respectively. Under optimized reaction conditions, the AuNC-based immunofluorescent-aggregation assay had a determination range between 7.0 × 103 and 3.0 × 108 CFU/mL, a limit of detection of 1.0 × 103 CFU/mL and an assay response time of 3 min. The technique delivered good results in assessing real samples.

Ultrasensitive Glutathione-Mediated Facile Split-Type Electrochemiluminescence Nanoswitch Sensing Platform.

Seeking for an advanced electrochemiluminescence (ECL) platform is still an active and continuous theme in the ECL-sensing realm. This work outlines a femtomolar-level and highly selective glutathione (GSH) and adenosine triphosphate (ATP) ECL assay strategy using a facile split-type gold nanocluster (AuNC) probe-based ECL platform. The system utilizes GSH as an efficient etching agent to turn on the MnO2/AuNC-based ECL nanoswitch platform. This method successfully achieves an ultrasensitive detection of GSH, which significantly outperformed other sensors. Based on the above excellent results, GSH-related biological assays have been further established by taking ATP as a model. Combined with the high catalytic oxidation ability of DNAzyme, this ECL sensor can realize ATP assay as low as 1.4 fmol without other complicated exonuclease amplification strategies. Thus, we successfully achieved an ultrahigh sensitivity, extremely wide dynamic range, great simplicity, and strong anti-interference detection of ATP. In addition, the actual sample detection for GSH and ATP exhibits satisfactory results. We believe that our proposed high-performance platform will provide more possibilities for the detection of other GSH-related substances and show great prospect in disease diagnosis and biochemical research.