Dual-reporter fluorescent probe for precise identification of liver cancer by sequentially responding to carboxylesterase and polarity.

Early treatment significantly improves the survival rate of liver cancer patients, so the development of early diagnostic methods for liver cancer is urgent. Liver cancer can develop from viral hepatitis, alcoholic liver, and fatty liver, thus making the above diseases share common features such as elevated viscosity, reactive oxygen species, and reactive nitrogen species. Therefore, accurate differentiation between other liver diseases and liver cancer is both a paramount practical need and challenging. Numerous fluorescent probes have been reported for the diagnosis of liver cancer by detecting a single biomarker, but these probes lack specificity for liver cancer in complex biological systems. Obviously, using multiple liver cancer biomarkers as the basis for judgment can dramatically improve diagnostic accuracy. Herein, we report the first fluorescent probe, LD-TCE, that sequentially detects carboxylesterase (CE) and lipid droplet polarity in liver cancer cells with high sensitivity and selectivity, with linear detection of CE in the range of 0-6 U/mL and a 65-fold fluorescence enhancement in response to polarity. The probe first reacts with CE and releases weak fluorescence, which is then dramatically enhanced due to the decrease in lipid droplet polarity in liver cancer cells. This approach allows the probe to enable specific imaging of liver cancer with higher contrast and accuracy. The probe successfully achieved the screening of liver cancer cells and the precise identification of liver cancer in mice. More importantly, it is not disturbed by liver fibrosis, which is a common pathological feature of many liver diseases. We believe that the LD-TCE is expected to be a powerful tool for early diagnosis of liver cancer.

Are microplastics in livestock and poultry manure an emerging threat to agricultural soil safety?

Microplastics (MPs) have attracted much attention in recent years, due to the difficulty of degradation and threats to ecological systems and humans. Based on the analysis of 1429 articles on MPs in soil, we found that we know little about the behavior and fate of manure-born MPs from the livestock and poultry production systems to agriculture soils. This review summarizes the analytical methods for sampling, separation, and identification and the occurrence of MPs in livestock and poultry manure, mainly based on 7 surveys related to manure-born MPs. Then, the sources, fate, and environmental risks of MPs in livestock and poultry manure are discussed. MPs, heavy metals, pathogens, antibiotic resistance genes, and persistent organic pollutants are common pollutants in livestock and poultry manure. Worse, manure-born MPs will become smaller, rougher, and more numerous and could easily form more toxic compound pollution after complicated processes of manure treatment, which seriously threatens agricultural soil safety. Finally, an outlook is offered for future research. We hope this article to attract attention to the risks of MPs in livestock and poultry manure and provide a reference for future research.

Multimodal MRI for Estimating Her-2 Gene Expression in Endometrial Cancer.

PURPOSE: To assess the value of multimodal MRI, including amide proton transfer-weighted imaging (APT), diffusion kurtosis imaging (DKI), and T2 mapping sequences for estimating human epidermal growth factor receptor-2 (Her-2) expression in patients with endometrial cancer (EC). METHODS: A total of 54 patients with EC who underwent multimodal pelvic MRI followed by biopsy were retrospectively selected and divided into the Her-2 positive (n = 24) and Her-2 negative (n = 30) groups. Her-2 expression was confirmed by immunohistochemistry (IHC). Two observers measured APT, mean kurtosis (MK), mean diffusivity (MD), and T2 values for EC lesions. RESULTS: The Her-2 (+) group showed higher APT values and lower MD and T2 values than the Her-2 (-) group (all p < 0.05); there was no significant difference in MK values (p > 0.05). The area under the receiver operating characteristic curve (AUC) of APT, MD, T2, APT + T2, APT + MD, T2 + MD, and APT + MD + T2 models to identify the two groups of cases were 0.824, 0.695, 0.721, 0.824, 0.858, 0.782, and 0.860, respectively, and the diagnostic efficacy after combined APT + MD + T2 value was significantly higher than those of MD and T2 values individually (p = 0.018, 0.028); the diagnostic efficacy of the combination of APT + T2 values was significantly higher than that of T2 values separately (p = 0.028). Weak negative correlations were observed between APT and T2 values (r = -0.365, p = 0.007), moderate negative correlations between APT and MD values (r = -0.560, p < 0.001), and weak positive correlations between MD and T2 values (r = 0.336, p = 0.013). The APT values were independent predictors for assessing Her-2 expression in EC patients. CONCLUSION: The APT, DKI, and T2 mapping sequences can be used to preoperatively assess the Her-2 expression in EC, which can contribute to more precise treatment for clinical preoperative.

The rational utilization of organelle microenvironment for imaging of lysosomal SO2 with high fidelity.

Nowadays, more and more studies have linked the abnormal expression of active molecules in organelles with the occurrence of diseases, so there is an urgent need to develop tools for detecting active molecules in specific organelles. However, the recognition receptors of most organelle-targeting probes currently developed always remain active, which easily causes them to react with the analyte in the cytoplasm, thus misjudging the role of the analyte in the physiological and pathological processes. Therefore, it is of great significance to develop a new strategy for the design of probes capable of high-fidelity imaging of the analyte in specific organelles. Herein, we propose a new strategy that the activation of recognition receptors that can be triggered by the microenvironment of targeting organelles. Based on this strategy, we develop a novel lysosome-targeting fluorescent probe (Lyso-SO2) for imaging of sulfur dioxide (SO2) with high-fidelity in lysosomes. The inert probe is activated by the acidic environment in the lysosome and then responds quickly (<2 s) and sensitively (LOD = 0.34 µM) to SO2. This paradigm by taking full advantage of the features of the organelle microenvironment provides a promising methodology for developing organelle-targeting probes for high-fidelity imaging.

Microplastics removal and characteristics of a typical multi-combination and multi-stage constructed wetlands wastewater treatment plant in Changsha, China.

Wastewater treatment plants (WWTPs) are an important source of microplastics (MPs) entering the aquatic environment. As environmental awareness increases, WWTPs are gradually using constructed wetlands (CWs) in the depth treatment stage. There were few studies related to MPs removal efficiency of CWs, especially in multi-stage and multi-combinations CWs. Therefore, we studied MPs characteristics and removal in a typical CWs WWTP in Changsha, comparing the MPs removal efficiencies of different processes in a WWTP, focusing on the MPs abundance variation in different stages CWs. Result showed that the MPs removal efficiency of Phase Ⅰ was 87.72% and that of Phase II was 80.65%. Approximate estimates showed that the daily discharge of MPs reached 7.20 * 108 items. The MPs removal efficiency of vertical flow CWs was 25.71%. The MPs removal efficiencies of secondary and tertiary horizontal subsurface flow CWs (HSSFCWs) were 32.00% and 21.43%. The MPs removal efficiencies of secondary and tertiary surface flow CWs were 23.53% and 12.50%. The MPs removal efficiencies of three bio-ponds were -23.08%, -12.90%, and -27.27%. Combined system of bio-pond + CWs reduced the MPs removal efficiency. The most dominant shape of MPs in wastewater was fibers. The most common MPs were polyethylene and polystyrene. The primary treatment in the Changsha WWTP had the highest MPs removal efficiency. Results of this investigation showed the multi-combination and multi-stage CWs WWTP can remove most of MPs in influent, which greatly reduced the amount of MPs discharged into the aquatic environment through WWTP and provided data for analyzing the distribution of MPs in the aquatic environment.

Rational design of a water-soluble TICT-AIEE-active fluorescent probe for mercury ion detection.

Considering that mercury ions (Hg2+) have long been a threat to human health and the environment due to their persistence, mobility and bioenrichment, the detection and removal of Hg2+ is of great significance. Therefore, a simple water-soluble naphthalimide derived fluorescent dye with AIEE characteristics was reasonably constructed based on twisted intramolecular charge transfer (TICT) mechanism, a series of probes were synthesized to demonstrate this mechanism. The probe NIDEA (naphthalimide-diethanolamine) bonding Hg2+ through the specific combination of the N-unsubstituted naphthalimide group and Hg2+ to form a classic "imide-Hg-imide" structure. Moreover, the introduction of diethanolamine moiety enhanced the water-solubility of the probe, and also made the dye molecule possess the feature of AIEE. The fluorescence titration experiment showed that there were two good linear relationships between the fluorescence intensity of the probe NIDEA and the concentration of Hg2+ in the range of 0-2.5 µM and 2.5-7.5 µM, and the limit of detection was 46.7 nM. Also, the probe could detect Hg2+ in aqueous solution sensitively, ensuring its application in the actual water sample in the environment and living cells. At the same time, NIDEA can be used to detect Hg2+ by Tyndall effect (TE) without limitation of instrument and technology, the limit of detection was 20.9 nM. Furthermore, this paradigm by introduction of the highly effective TICT structure supports a promising methodology for the construction of simple water-soluble AIE/AIEE-active probes.

In Situ Observation of Lysosomal Hypobromous Acid Fluctuations in the Brain of Mice with Depression Phenotypes by Two-Photon Fluorescence Imaging.

Excessive oxidative stress is the main cause of neurotransmitter metabolism disorder in the brain with depression. Lysosomal hypobromic acid (HOBr) is an important reactive oxygen species produced in oxidative stress. Its abnormal content can lead to macromolecular damage and neurodegenerative diseases. However, due to the high reactivity and low concentration of HOBr and the lack of in situ imaging methods, the role of HOBr in depression is not clear. Herein, based on the HOBr-initiated aromatic substitution of a tertiary amine, we developed a novel two-photon (TP) fluorescence probe (NH-HOBr) for real-time visual monitoring of trace HOBr in living systems. NH-HOBr introduces N-(2-aminoethyl)-morpholine as a new recognition receptor for HOBr and a targeting group for lysosomes. It not only has excellent selectivity compared with other biomolecules (including hypochlorous acid), fast response (≤5 s) and high sensitivity (LOD = 15 nM) but also realizes sensitive detection of HOBr in cells, zebrafish, and mice tissues. It is worth noting that the in situ TP fluorescence imaging of mouse brain reveals the positive correlation between HOBr content and depression phenotype for the first time, providing strong direct evidence for the relationship between oxidative stress and depression. This work can provide reference to further study depression and the pathological mechanism of HOBr. In addition, HOBr-initiated aromatic substitution of a tertiary amine provides a new idea for the construction of specific and sensitive HOBr probes.

Concise Biothiol-Activatable HPQ-NBD Conjugate as a Targeted Theranostic Probe for Tumor Cells.

Cancer, as a malignant tumor, seriously endangers human health. The study of cancer diagnosis and therapy has great practical significance. The development of theranostic agents has become a very important research topic. Nevertheless, some existing agents still have imperfections, such as complex structures and difficult syntheses. Therefore, it is urgent for researchers to develop simple novel theranostic agents. In this study, the precipitated fluorophore HAPQ was used as a simple drug molecule for the first time and combined with NBD-Cl to construct a simple and efficient theranostic probe (HAPQ-NBD). The theranostic probe can distinguish between tumor cells and normal cells based on the higher levels of biothiol in tumor cells. In addition, the probe can use biothiol as a control switch to release higher levels of precipitated fluorophore HAPQ in tumor cells, leading to selective high toxicity to tumor cells, thus achieving the goal of selectively killing tumor cells. The construction of probe HAPQ-NBD provides a practical tool for the diagnosis and therapy of cancer. It is expected that the development and utilization of precipitated fluorophore will provide a new method and strategy for cancer diagnosis and therapy.

A new-type HOCl-activatable fluorescent probe and its applications in water environment and biosystems.

The outbreak and spread of Corona Virus Disease 2019 (COVID-19) has led to a significant increase in the consumption of sodium hypochlorite (NaOCl) disinfectants. NaOCl hydrolyzes to produce hypochlorous acid (HOCl) to kill viruses, which is a relatively efficient chlorine-based disinfectant commonly used in public disinfection. While people enjoy the convenience of NaOCl disinfection, excessive and indiscriminate use of it will affect the water environment and threaten human health. Importantly, HOCl is an indispensable reactive oxygen species (ROS) in human body. Whether its concentration is normal or not is closely related to human health. Excessive production of HOCl in the body contributes to some inflammatory diseases and even cancer. Also, we noticed that the concentration of ROS in cancer cells is about 10 times higher than that in normal cells. Herein, we developed a HOCl-activatable biotinylated dual-function fluorescent probe BTH. For this probe, we introduced biotin on the naphthalimide fluorophore, which increased the water solubility and enabled the probe to aggregate in cancer cells by targeting specific receptor overexpressed on the surface of cancer cell membrane. After reacting to HOCl, the p-aminophenylether moiety of this probe was oxidatively removed and the fluorescence of the probe was recovered. As expected, in the PBS solution with pH of 7.4, BTH could give full play to the performance of detecting HOCl, and it has made achievements in detecting the concentration of HOCl in actual water samples. Besides that, BTH had effectively distinguished between cancer cells and normal cells through a dual-function discrimination strategy, which used biotin to enrich the probe in cancer cells and reacted with overexpressed HOCl in cancer cells. Importantly, this dual-function discrimination strategy could obtain the precision detection of cancer cells, thereby offering assistance for improving the accuracy of early cancer diagnosis.

Rational design of a fluorescent probe and its applications of imaging and distinguishing between exogenous and endogenous H2S in living cells.

Hydrogen sulfide (H2S), a recognized environmental pollutant, comes from a wide range of sources. For example, H2S will be produced in the process of plant protein corruption, the decomposition of domestic sewage and garbage, food processing (wine brewing), etc. and once the concentration is too high, it will cause significant damage of environment and human body. Besides H2S is an important gas signal molecule in vivo, which can be transferred through lipid membrane. Its existence level is closely related to many diseases. If we can "visually" trace the transmembrane transmission of hydrogen sulfide, it will be very helpful for the study of oxidative stress processes, cell protection, signal transduction and related diseases closely related to H2S. Although some probes can detect H2S in environment, cytoplasm and organelles, there are few reports on the release and internalization of H2S. In this work, we report a H2S fluorescence probe that can retain on the cell membrane, named PCM. The probe PCM can not only detect endogenous and exogenous H2S, but also distinguish them, this provides a general strategy for the construction of probes to detect other biomarkers. In addition, PCM has been successfully applied to the detection of endogenous and exogenous H2S in zebrafish, which has the potential to become a new chemical tool and provide help for the research of H2S-related diseases.

An Integrated Fluorescent Probe for Ratiometric Detection of Glutathione in the Golgi Apparatus and Activated Organelle-Targeted Therapy.

Cancer is a serious threat to human health, and there is an urgent need to develop new treatment methods to overcome it. Organelle targeting therapy, as a highly effective and less toxic side effect treatment strategy, has great research significance and development prospects. Being an essential organelle, the Golgi apparatus plays a particularly major role in the growth of cancer cells. Acting as an indispensable and highly expressed antioxidant in cancer cells, glutathione (GSH) also contributes greatly during the Golgi oxidative stress. Therefore, it counts for much to track the changes of GSH concentration in Golgi for monitoring the occurrence and development of tumor cells, and exploring Golgi-targeted therapy is also extremely important for effective treatment of cancer. In this work, we designed and synthesized a simple Golgi-targeting fluorescent probe GT-GSH for accurately detecting GSH. The probe GT-GSH reacting with GSH decomposes toxic substances to Golgi, thereby killing cancer cells. At the same time, the ratiometric fluorescent probe can detect the concentration changes of GSH in Golgi stress with high sensitivity and selectivity in living cells. Therefore, such a GSH-responsive fluorescent probe with a Golgi-targeted therapy effect gives a new method for accurate treatment of cancer.

A simple sensitive ratiometric fluorescent probe for the detection of mercury ions in living cells and zebrafish.

Mercury, as a highly toxic heavy metal, can cause very serious harm to human health and even death in severe cases. Therefore, we synthesized a novel ratiometric fluorescent probe for detecting mercury ions, with mercaptoethanol as the recognition receptor. Probe CMER could determine mercury ions in 0-1.6 µM and the detection limit is 7.6 nM. Moreover, CMER manifested a fast response for Hg2+ (within 5 s) and simultaneously observed that the color changed from light yellow to orange by naked eye. In addition to these preeminent spectral properties, the probe also had satisfactory bioimaging results in RAW 264.7 macrophage cells and zebrafish.

A coumarin-based fluorescent probe for Hg2+ and its application in living cells and zebrafish.

Mercury (Hg) is a heavy metal with high toxicity and easy migration; it can be enriched through the food chain, and cause serious threats to the natural environment and human health. So, the development of a method that can be used to detect mercury ions (Hg2+ ) in the environment, in cells, and in organisms is very important. Here, a new 7-hydroxycoumarin-derived carbonothioate-based probe (CC-Hg) was designed and synthesized for detection of Hg2+ . After addition of Hg2+ , a large fluorescence enhancement was observed due to the formation of 7-hydroxyl, which reinforced the intramolecular charge transfer process. The CC-Hg probe had good water solubility and selectivity. Moreover, the probe was able to detect Hg2+ quantitatively over the concentration range 0-2 µM and with a detection limit of 7.9 nM. Importantly, we successfully applied the probe to detect Hg2+ in water samples, in living cells, and in zebrafish. The experimental results demonstrated its potential value in practical applications.

A Highly Selective and Ultrasensitive Fluorescent Probe for Monitoring Hg2+ and Its Applications in Real Water Samples.

Mercury ions as high toxic pollutants have received wide-spread attention because of their poisonousness, persistence and enrichment. To better understand the distribution of mercury species and supplement more detailed toxicological research, it is necessary to develop some methods for monitoring mercury ions with high sensitivity and selectivity. Therefore, a simple rhodol-based highly selective fluorescent probe, RH-Hg, has been developed for monitoring Hg2+ with thiocarbamate as the recognition receptor. The probe RH-Hg can quantificationally detect mercury ions in aqueous solution assisted by hydrogen peroxide (H2O2), and it can discriminate Hg2+ through "naked-eye" observation of the color changes from light orange to dark pink. Finally, the practical applications of the probe RH-Hg in the river water further demonstrated that it will be an effective and economical tool for monitoring the distribution of Hg2+ in the environment.

Population pharmacokinetic-pharmacodynamic (PopPK/PD) modeling of risperidone and its active metabolite in Chinese schizophrenia patients.

PURPOSE: Risperidone is a second-generation antipsychotic agent commonly used in the treatment of ~ 31.1% of schizophrenia patients in China, it is the most commonly-prescribed antipsychotic agent. Despite the abundant use of risperidone, population pharmacokinetic-pharmacodynamic models of risperidone have not been performed in Chinese schizophrenia patients. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PopPK/PD) model to describe the PK behavior and efficacy of risperidone and 9-hydroxy-risperidone (active metabolite) in Chinese patients. METHODS: Plasma concentration data (702 measurements from 131 patients) and positive and negative syndrome scale (PANSS) scores (258 observations from 56 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCEI). The influence of potential covariates was evaluated. Model robustness was assessed using external validation, normalized prediction distribution error, nonparametric bootstrap, and visual predictive check approaches. RESULTS: Risperidone concentration data were well described by a one-compartmental model incorporating an additional compartment that refers to the concentration profiles of 9-hydroxy-risperidone. A complex absorption procedure was incorporated into the model to describe the metabolism of risperidone to 9-hydroxy-risperidone in the gastrointestinal (GI) tract. A binomial distribution in the estimated clearance (CL) of risperidone has been identified in our model. Decrease in PANSS score along with total AUC (AUCtotal) of risperidone and 9-hydroxy-risperidone was best characterized by an Emax model with 3 transit compartments describing the delay of drug effect. CONCLUSIONS: Considerable differences in PK behavior and drug effect of risperidone have been identified among Chinese extensive metabolizing (EM) and poor metabolizing (PM) patients. This PopPK/PD model may fulfill individualized treatment in clinical practice and may potentially be transferred to other antipsychotic therapies.