A High-Efficiency Bioorthogonal Tumor-Membrane Reactor for In Situ Selective and Sustained Prodrug Activation.

The site-specific activation of bioorthogonal prodrugs has provided great opportunities for reducing the severe side effects of chemotherapy. However, the precise control of activation location, sustained drug production at the target site, and high bioorthogonal reaction efficiency in vivo remain great challenges. Here, we propose the construction of tumor cell membrane reactors in vivo to solve the above problems. Specifically, tumor-targeted liposomes with efficient membrane fusion capabilities are generated to install the bioorthogonal trigger, the amphiphilic tetrazine derivative, on the surface of tumor cells. These predecorated tumor cells act as many living reactors, transforming the tumor into a "drug factory" that in situ activates an externally delivered bioorthogonal prodrug, for example intratumorally injected transcyclooctene-caged doxorubicin. In contrast to the rapid elimination of cargo that is encapsulated and delivered by liposomes, these reactors permit stable retention of bioorthogonal triggers in tumor for 96 h after a single dose of liposomes via intravenous injection, allowing sustained generation of doxorubicin. Interestingly, an additional supplement of liposomes will compensate for the trigger consumed by the reaction and significantly improve the efficiency of the local reaction. This strategy provides a solution to the efficacy versus safety dilemma of tumor chemotherapy.

Real-Time Imaging of Hepatic Inflammation Using Hydrogen Sulfide-Activatable Second Near-Infrared Luminescent Nanoprobes.

The sensing and visualized monitoring of hydrogen sulfide (H2S) in vivo is crucial to understand its physiological and pathological roles in human health and diseases. Common methods for H2S detection require the destruction of the biosamples and are not suitable to be applied in vivo. In this Communication, we report a "turn-on" second near-infrared (NIR-II) luminescent approach for sensitive, real-time, and in situ H2S detection, which is based on the absorption competition between the H2S-responsive chromophores (compound 1) and the NIR-II luminescent lanthanide nanoparticles. Specifically, the luminescence was suppressed by compound 1 due to the competitive absorption of the incident light. In the presence of H2S, the compound 1 was bleached to recover the luminescence. Thanks to the deep tissue penetration depth and the low absorbance/scattering on biological samples of the NIR-II nanoprobes, the monitoring of the endogenous H2S in lipopolysaccharide-induced liver inflammation was achieved, which is unattainable by the conventional histopathological and serological approaches.

Road Injuries Associated With Cellular Phone Use While Walking or Riding a Bicycle or an Electric Bicycle: A Case-Crossover Study.

Vulnerable road users (pedestrians, bicyclists, and motorcyclists) account for an increasing proportion of traffic injuries. We used a case-crossover study design to examine the association between cell-phone usage and traffic injuries among pedestrians, bicyclists, and electric bicycle riders during the course of their travel. We studied 643 pedestrians, bike riders, and electric bike riders aged 10-35 years who were involved in a road injury, visited the emergency department in one of the 3 hospitals in Shanghai, China, in 2019, and owned a cell phone. Half of the participants (n = 323; 50.2%) had used a cell phone within 1 minute before the injury happened. A pedestrian's or rider's use of a mobile phone up to 1 minute before a road injury was associated with a 3-fold increase in the likelihood of injury (odds ratio = 3.00, 95% confidence interval: 2.04, 4.42; P < 0.001). The finding was consistent across subgroups by sex, occupation, reason for travel, mode of transportation, and location of injury. Use of a cell phone when walking or riding was associated with an increased risk of road injury. Measures should be taken to make people aware of this detrimental impact on the risk of road injury.

Lanthanide Metal-Organic Framework-Based Fluorescent Sensor Arrays to Discriminate and Quantify Ingredients of Natural Medicine.

The discrimination and quantification of the ingredients from natural medicines are a challenging issue due to their complicated and various structures. Metal-organic frameworks (MOFs) have shown great promise in sensing applications. Here, we report a fluorescent sensor array for rapid identification of some natural compounds using a sensor array composed of four kinds of lanthanide (Eu3+ and Tb3+) fluorescent MOFs (Ln-MOFs), which have diversified fluorescent responses to 26 active/toxic compounds including 12 saponins, 7 flavonoids, 3 stilbenes, and 4 anthraquinones. The fluorescence of the Ln-MOFs after reaction with the compounds was summarized as datasets and processed by principle component analysis (PCA) and hierarchical cluster analysis (HCA) methods. The corresponding responses of the 4 types of compounds are well separated on 2D/3D PCA score plots and HCA dendrograms. We have also tested typical blind samples by concentration-dependent PCA, and an accuracy of 100% was obtained. In addition, the response mechanisms of the Ln-MOFs to the compounds were also studied. Compared with traditional methods using liquid chromatography-mass spectrometry, the developed fluorescent sensor array provides a more efficient and economic strategy to discriminate various active/toxic ingredients in natural medicine.

Pharmacokinetic Advantage of ASD Device Promote Drug Absorption through the Epicardium.

PURPOSE: Due to low therapeutic efficacy and severe adverse reaction of systemic administration for coronary heart disease (CHD) therapy, we designed a novel local target delivery system, called Active hydraulic ventricular Support Drug delivery system (ASD). This study aims to investigate the potential advantages of ASD compared to intrapericardial (IPC) injection and factors affecting drug absorption through epicardium. METHODS: Liposoluble, water soluble and viscous solutions of cyanine 5 (Cy5) fluorescent dye were delivered individually through ASD and IPC in Sprague-Dawley (SD) rats and then tissues were isolated and observed by in vivo imaging system. Atria and ventricles of the heart were taken for the paraffin section and observed under a fluorescence microscope. RESULTS: The fluorescence intensity of Cy5 injected by ASD distributed in the heart was significantly higher than IPC injection. Whereas, the fluorescence signal spread in other tissues such as lung, liver, spleen, and kidney of ASD groups was much weaker. Moreover, when choosing liposoluble and viscous Cy5, the intensity of the heart turned stronger and fluorescence dye distributed in other tissues was lesser. CONCLUSIONS: The application of ASD device may provide a promising route of drug delivery for CHD. Furthermore, increasing viscosity of the solution and liposolublity of the drug was beneficial to facilitate drug absorption through the epicardium.

A General Strategy for Hollow Metal-Phytate Coordination Complex Micropolyhedra Enabled by Cation Exchange.

The ability to incorporate functional metal ions (Mn+ ) into metal-organic coordination complexes adds remarkable flexibility in the synthesis of multifunctional organic-inorganic hybrid materials with tailorable electronic, optical, and magnetic properties. We report the cation-exchanged synthesis of a diverse range of hollow Mn+ -phytate (PA) micropolyhedra via the use of hollow Co2+ -PA polyhedral networks as templates at room temperature. The attributes of the incoming Mn+ , namely Lewis acidity and ionic radius, control the exchange of the parent Co2+ ions and the degree of morphological deformation of the resulting hollow micropolyhedra. New functions can be obtained for both completely and partially exchanged products, as supported by the observation of Ln3+ (Ln3+ =Tb3+ , Eu3+ , and Sm3+ ) luminescence from as-prepared hollow Ln3+ -PA micropolyhedra after surface modification with dipicolinic acid as an antenna. Moreover, Fe3+ - and Mn2+ -PA polyhedral complexes were employed as magnetic contrast agents.

De Novo Design of Chemical Stability Near-Infrared Molecular Probes for High-Fidelity Hepatotoxicity Evaluation In Vivo.

Near-infrared (NIR) fluorescence imaging technique is garnering increasing research attention due to various advantages. However, most NIR fluorescent probes still suffer from a false signals problem owing to their instability in real application. Especially in a pathological environment, many NIR probes can be easily destroyed due to the excessive generation of highly reactive species and causing a distorted false signal. Herein, we proposed an approach for developing a new stable NIR dye platform with an optically tunable group to eliminate false signals using the combination of dyes screening and rational design strategy. The conception is validated by the construction of two high-fidelity NIR fluorescent probes (NIR-LAP and NIR-ONOO-) sensing leucine aminopeptidase (LAP) and peroxynitrite (ONOO-), the markers of hepatotoxicity. These probes (NIR-LAP and NIR-ONOO-) were demonstrated to sensitively and accurately monitor LAP and ONOO- (detection limit: 80 mU/L for LAP and 90 nM for ONOO-), thereby allowing one to precisely evaluate drug-induced hepatotoxicity. In addition, based on the fluctuation of LAP, the therapeutic efficacy of six hepatoprotective medicines for acetaminophen-induced hepatotoxicity was analyzed in vivo. We anticipate the high-fidelity NIR dye platform with an optically tunable group could provide a convenient and efficient tool for the development of future probes applied in the pathological environment.

Chromophore-Modified Highly Selective Ratiometric Upconversion Nanoprobes for Detection of ONOO- -Related Hepatotoxicity In Vivo.

Acute hepatitis is a major problem affecting public health and has attracted more and more attention. Generally, as the standard means, blood tests are taken for evaluating hepatitis. However, such tests fail to accurately reflect the level of hepatitis in vivo. Herein, two highly selective ratiometric fluorescent probes are designed to track peroxynitrite (ONOO- ) as the hepatitis indicator, and further evaluate acute liver injury in vivo through dye-grafted upconversion nanoparticles (UCNPs). Specifically, upconversion luminescence of nanoprobes at 540 or 660 nm can be quenched by the designed and synthesized chromophore E-CC or H-CC, that can be destroyed by ONOO- via energy transfer (ET) process, while the upconversion luminescence intensity at 810 nm remains the same. Thus, the developed nanoprobes can be used for ratiometric detection (I540 /I660 or I660 /I810 ) of ONOO- . Moreover, the developed near infrared ratiometric nanoprobes can highly selectively detect ONOO- , which can eliminate the interference of HOCl and SO32- . Finally, it is demonstrated that this highly selective ratiometric nanosystem can achieve effective detection of ONOO- in living cells and CCl4 -induced acute liver injury models. It provides some reference value for clinical detection of hepatotoxicity.

Gold nanoparticle-based detection of dopamine based on fluorescence resonance energy transfer between a 4-(4-dialkylaminostyryl)pyridinium derived fluorophore and citrate-capped gold nanoparticles.

A colorimetric/fluorometric dual-signal assay is described for the determination of dopamine (DA). A nanoprobe was obtained by linking a 4-(4-dialkylaminostyryl)pyridinium derived fluorophore to citrate-capped gold nanoparticles (AuNPs). The fluorescence of the fluorophore is quenched by the AuNPs via fluorescence resonance energy transfe. In the presence of DA, the catechol group of DA can absorb on the surface of AuNPs to induce aggregation, which is accompanied by a color change from red to blue. The yellow fluorescence of the fluorophore with excitation/emission maximum at 365/570 nm is recovered. The dual-signal detection allows the quantitative analysis of DA within 300 µM by the colorimetric method and 80 µM by the fluorometric method. The detection limits for the colorimetric/fluorometric methods are 1.85 µM and 0.29 µM, respectively. Quantitative determination of DA in spiked urine samples was successfully demonstrated, with recoveries ranging from 98.2 to 106.0%. Graphical abstract A colorimetric/fluorometric dual-signal assay is described for the determination of dopamine by linking a fluorophore to gold nanoparticles. The dopamine causes aggregation of the nanoparticles to induce color change, which is followed by the recovery of the fluorescence.

Silica Nanoparticle-Enhanced Fluorescent Sensor Array for Heavy Metal Ions Detection in Colloid Solution.

Sensitivity and detection limit are two vital factors that affect fluorophores-based sensing and imaging system. However, it remains a challenge to improve the sensitivity and detection limit of fluorophores, largely due to their limited response and photophysical properties. In this study, we report for the first time, a novel approach to enhance the sensitivity and detection limit of probes using silica nanoparticles, also known as silica nanoparticles-enhanced fluorescence (SiEF). SiEF can drastically improve the fluorescence intensities and detection limit of fluorophores. A SiEF-improved fluorescent sensor array for rapid and sensitive identification of different heavy metal ions is achieved, and a 3D spatial dispersion graph is obtained based on the SiEF-improved fluorescent sensor array, which provides a lower concentration dependent pattern than fluorophores alone, allowing qualitative, quantitative, and sensitive detection of heavy metal ions. Furthermore, with UV lamp irradiation of the sensor-metal ion mixtures, the output signals enable direct visual of heavy metal ions with low concentration. Thus, the SiEF approach provides a simple and practical strategy for fluorescent probes to improve their sensitivity and detection limit in analytes sensing.

Real-Time In†Vivo Hepatotoxicity Monitoring through Chromophore-Conjugated Photon-Upconverting Nanoprobes.

Drug toxicity is a long-standing concern of modern medicine. A typical anti-pain/fever drug paracetamol often causes hepatotoxicity due to peroxynitrite ONOO- . Conventional blood tests fail to offer real-time unambiguous visualization of such hepatotoxicity in vivo. Here we report a luminescent approach to evaluate acute hepatotoxicity in vivo by chromophore-conjugated upconversion nanoparticles. Upon injection, these nanoprobes mainly accumulate in the liver and the luminescence of nanoparticles remains suppressed owing to energy transfer to the chromophore. ONOO- can readily bleach the chromophore and thus recover the luminescence, the presence of ONOO- in the liver leads to fast restoring of the near-infrared emission. Taking advantages of the high tissue-penetration capability of near-infrared excitation/emission, these nanoprobes achieve real-time monitoring of hepatotoxicity in living animals, thereby providing a convenient screening strategy for assessing hepatotoxicity of synthetic drugs.

Boronic Acid: A Bio-Inspired Strategy To Increase the Sensitivity and Selectivity of Fluorescent NADH Probe.

Fluorescent probes have emerged as an essential tool in the molecular recognition events in biological systems; however, due to the complex structures of certain biomolecules, it remains a challenge to design small-molecule fluorescent probes with high sensitivity and selectivity. Inspired by the enzyme-catalyzed reaction between biomolecule and probe, we present a novel combination-reaction two-step sensing strategy to improve sensitivity and selectivity. Based on this strategy, we successfully prepared a turn-on fluorescent reduced nicotinamide adenine dinucleotide (NADH) probe, in which boronic acid was introduced to bind with NADH and subsequently accelerate the sensing process. This probe shows remarkably improved sensitivity (detection limit: 0.084 µM) and selectivity to NADH in the absence of any enzymes. In order to improve the practicality, the boronic acid was further modified to change the measurement conditions from alkalescent (pH 9.5) to physiological environment (pH 7.4). Utilizing these probes, we not only accurately quantified the NADH weight in a health care product but also evaluated intracellular NADH levels in live cell imaging. Thus, these bio-inspired fluorescent probes offer excellent tools for elucidating the roles of NADH in biological systems as well as a practical strategy to develop future sensitive and selective probes for complicated biomolecules.

A Multisite-Binding Switchable Fluorescent Probe for Monitoring Mitochondrial ATP Level Fluctuation in Live Cells.

Adenosine triphosphate (ATP), commonly produced in mitochondria, is required by almost all the living organisms; thus fluorescent probes for monitoring mitochondrial ATP levels fluctuation are essential and highly desired. Herein, we report a multisite-binding switchable fluorescent probe, ATP-Red 1, which selectively and rapidly responds to intracellular concentrations of ATP. Live-cell imaging indicated that ATP-Red 1 mainly localized to mitochondria with good biocompatibility and membrane penetration. In particular, with the help of ATP-Red 1, we successfully observed not only the decreased mitochondrial ATP levels in the presence of KCN and starvation state, but also the increased mitochondrial ATP levels in the early stage of cell apoptosis. These results indicate that ATP-Red 1 is a useful tool for investigating ATP-relevant biological processes.

Development of targetable two-photon fluorescent probes to image hypochlorous Acid in mitochondria and lysosome in live cell and inflamed mouse model.

Hypochlorous acid (HOCl), as a highly potent oxidant, is well-known as a key "killer" for pathogens in the innate immune system. Recently, mounting evidence indicates that intracellular HOCl plays additional important roles in regulating inflammation and cellular apoptosis. However, the organelle(s) involved in the distribution of HOCl remain unknown, causing difficulty to fully exploit its biological functions in cellular signaling pathways and various diseases. One of the main reasons lies in the lack of effective chemical tools to directly detect HOCl at subcellular levels due to low concentration, strong oxidization, and short lifetime of HOCl. Herein, the first two-photon fluorescent HOCl probe (TP-HOCl 1) and its mitochondria- (MITO-TP) and lysosome- (LYSO-TP) targetable derivatives for imaging mitochondrial and lysosomal HOCl were reported. These probes exhibit fast response (within seconds), good selectivity, and high sensitivity (<20 nM) toward HOCl. In live cell experiments, both probes MITO-TP and LYSO-TP were successfully applied to detect intracellular HOCl in corresponding organelles. In particular, the two-photon imaging of MITO-TP and LYSO-TP in murine model shows that higher amount of HOCl can be detected in both lysosome and mitochondria of macrophage cells during inflammation condition. Thus, these probes could not only help clarify the distribution of subcellular HOCl, but also serve as excellent tools to exploit and elucidate functions of HOCl at subcellular levels.

High-efficiency in vitro and in vivo detection of Zn2+ by dye-assembled upconversion nanoparticles.

Development of highly sensitive and selective sensing systems of divalent zinc ion (Zn(2+)) in organisms has been a growing interest in the past decades owing to its pivotal role in cellular metabolism, apoptosis, and neurotransmission. Herein, we report the rational design and synthesis of a Zn(2+) fluorescent-based probe by assembling lanthanide-doped upconversion nanoparticles (UCNPs) with chromophores. Specifically, upconversion luminescence (UCL) can be effectively quenched by the chromophores on the surface of nanoparticles via a fluorescence resonant energy transfer (FRET) process and subsequently recovered upon the addition of Zn(2+), thus allowing for quantitative monitoring of Zn(2+). Importantly, the sensing system enables detection of Zn(2+) in real biological samples. We demonstrate that this chromophore-UCNP nanosystem is capable of implementing an efficient in vitro and in vivo detection of Zn(2+) in mouse brain slice with Alzheimer's disease and zebrafish, respectively.

An artificial tongue fluorescent sensor array for identification and quantitation of various heavy metal ions.

Herein, a small-molecule fluorescent sensor array for rapid identification of seven heavy metal ions was designed and synthesized, with its sensing mechanism mimicking that of a tongue. The photoinduced electron transfer and intramolecular charge transfer mechanism result in combinatorial interactions between sensor array and heavy metal ions, which lead to diversified fluorescence wavelength shifts and emission intensity changes. Upon principle component analysis (PCA), this result renders clear identification of each heavy metal ion on a 3D spatial dispersion graph. Further exploration provides a concentration-dependent pattern, allowing both qualitative and quantitative measurements of heavy metal ions. On the basis of this information, a "safe-zone" concept was proposed, which provides rapid exclusion of versatile hazardous species from clean water samples based on toxicity characteristic leaching procedure standards. This type of small-molecule fluorescent sensor array could open a new avenue for multiple heavy metal ion detection and simplified water quality analysis.

Multicriteria decision-making approach with hesitant interval-valued intuitionistic fuzzy sets.

The definition of hesitant interval-valued intuitionistic fuzzy sets (HIVIFSs) is developed based on interval-valued intuitionistic fuzzy sets (IVIFSs) and hesitant fuzzy sets (HFSs). Then, some operations on HIVIFSs are introduced in detail, and their properties are further discussed. In addition, some hesitant interval-valued intuitionistic fuzzy number aggregation operators based on t-conorms and t-norms are proposed, which can be used to aggregate decision-makers' information in multicriteria decision-making (MCDM) problems. Some valuable proposals of these operators are studied. In particular, based on algebraic and Einstein t-conorms and t-norms, some hesitant interval-valued intuitionistic fuzzy algebraic aggregation operators and Einstein aggregation operators can be obtained, respectively. Furthermore, an approach of MCDM problems based on the proposed aggregation operators is given using hesitant interval-valued intuitionistic fuzzy information. Finally, an illustrative example is provided to demonstrate the applicability and effectiveness of the developed approach, and the study is supported by a sensitivity analysis and a comparison analysis.

Association of dietary intake and serum concentration of omega-3 fatty acids on celiac disease: evidence from observational study and Mendelian randomization.

OBJECTIVE: The association between omega-3 fatty acids (O3FA) and celiac disease lacks sufficient investigation. METHODS: Utilizing data gleaned from the 2009 to 2014 National Health and Nutrition Examination Survey (NHANES), this research comprises a sample of 13 403 adults, each aged 20 years and above. We conducted a multivariable logistic regression analysis to assess the association between dietary intake of O3FA and celiac disease. Subsequently, a two-sample Mendelian randomization was performed to estimate the unconfounded causal relationship between serum O3FA and celiac disease. The principal analytical strategy utilized the inverse-variance weighted methodology. RESULTS: In this cross-sectional study, 48 occurrences (0.36%) of celiac disease were encompassed. In the multivariable model, there was no association between dietary intake of O3FA and cases of celiac disease (odds ratio: 1.12, 95% confidence interval: 0.47-2.66, P = 0.792). However, serum levels of O3FA determined by genetic assay were correlated with celiac disease (inverse-variance weighted, ß = 0.2439, P = 0.0287), with no evidence of horizontal pleiotropy (P = 0.3689). CONCLUSION: The dietary consumption of O3FA did not exhibit an association with the risk of celiac disease in this cross-sectional investigation. However, a correlation between celiac disease and serum levels of O3FA was observed in the Mendelian randomization. Further investigations, including human clinical trials, are warranted.

Bromide triggers efficient peroxymonosulfate activation for phosphonate degradation.

Phosphonates have received a widespread attention in wastewater treatment due to their potential threat to the water environment. Advanced oxidation processes (AOPs) are feasible methods to degrade phosphonates, and most of the coexisting substances in water show a negative factor during their oxidation. However, the effect of bromide (Br-) on the degradation of phosphonates in peroxymonosulfate (PMS) activation is still unclear. Herein, using 1-hydroxyethane 1,1-diphosphonic acid (HEDP) as a target phosphonate, Br- could remarkably enhance the degradation of HEDP in PMS activation compared to the PMS alone. Under the condition of pH = 7.0, the optimal degradation efficiency of HEDP is 84.8% in the PMS/Br- process after 30-min reaction, whereas no significant oxidation is obtained in the PMS/I- and PMS/Cl- processes. Multiple experiments (i.e., electron paramagnetic resonance (EPR), radical quenching experiments and chemical probs) confirm that free bromine, SO4•- and HO• paly a minor role in HEDP removal, and bromine radical species make a dominant responsible for HEDP oxidation. Additionally, NO3-, SO42-, Cl-, and HCO3- have a little effect on the degradation of HEDP, but the HEDP removal is greatly inhibited in the presence of humic acid (HA). However, the degradation efficiency of HEDP using PMS/Br- process in river and sewage is a much higher than UV/persulfate (PDS) and UV/H2O2 processes. This study provides a new sight into the effect of Br- on the degradation phosphonates in PMS activation process.

Long-circulating nanoparticles as passive targeting nanocarriers for the treatment of thrombosis.

Thrombosis is the major cause of cardiovascular diseases. Only a small subset of patients could benefit from thrombolytic therapy due to the high bleeding risk brought about by the repeated administration of thrombolytic drugs. Nanoparticles with targeting ligands have been developed as nanocarriers of thrombolytic drugs to deliver the drug to the thrombus through active targeting. However, the passive targeting effect of nanoparticles on the thrombus is yet to be investigated. Herein, we prepared silica cross-linked micelles (SCLMs) with a long blood circulation half-life as drug carriers to target the thrombus through passive targeting. Compared with SCLMs modified with an active targeting ligand cRGD, the SCLMs exhibited similar targeting behavior to the thrombus in vivo. Loaded with the thrombolytic drug tirofiban, the passive targeting SCLMs showed a comparable therapeutic effect to cRGD-modified SCLMs in a mice model with pulmonary embolism and arterial thrombosis.