A Rationally Designed Prodrug for the Fluorogenic Labeling of Albumin and Theranostic Effects on Drug-Induced Liver Injury.

The development of small-molecular fluorogenic tools for the chemo-selective labeling of proteins in live cells is important for the evaluation of intracellular redox homeostasis. Dynamic imaging of human serum albumin (HSA), an antioxidant protein under oxidative stress with concomitant release of antioxidant drugs to maintain redox homeostasis, affords potential opportunities for disease diagnosis and treatment. In this work, we developed a nonfluorogenic prodrug named TPA-NAC, by introducing N-acetyl-l-cysteine (NAC) into a conjugated acceptor skeleton. Through combined thiol and amino addition, coupling with HSA results in fluorescence turn-on and drug release. It was reasoned that the restricted intramolecular motion of the probe under an HSA microenvironment after covalent bonding inhibited the nonradiative transitions. Furthermore, the biocompatibility and photochemical properties of TPA-NAC enabled it to image exogenous and endogenous HSA in living cells in a wash-free manner. Additionally, the released drug evoked upregulation of superoxide dismutase (SOD), which synergistically eliminated reactive oxygen species in a drug-induced liver injury model. This study provides insights into the design of new theranostic fluorescent prodrugs for chemo-selective protein labeling and disease treatments.

Changing Trends in the Global Burden of Cataract Over the Past 30 Years: Retrospective Data Analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Cataracts now account for the largest proportion of the global burden of blindness and vision loss. Understanding the changing trends in the global burden of cataracts over the past 30 years and the next 15 years is of clear significance for the prevention and control of cataracts in key populations. As far as we know, research on the future burden of cataracts is lacking. OBJECTIVE: This study aims to assess the global burden of cataracts over the past 30 years by using age-period-cohort modeling and to estimate trends in the next 15 years. METHODS: Data were obtained from the Global Burden of Disease Study 2019, the United Nations Development Programme, and the WHO (World Health Organization) Global Health Observatory data repository. The assessment of trends and disparities in the number and rate of disability-adjusted life years (DALYs) for cataracts from 1990 to 2019 was conducted. The association between the age-standardized DALY rate (ASDR) and the socio-demographic index (SDI), human development index (HDI), national levels of particulate matter <2.5 µm in diameter (PM2.5), and ambient ultraviolet radiation (UVR) was determined using linear regression analysis. Additionally, we used the Nordpred (Harald Fekjær and Bjørn Møller) age-period-cohort model to predict the cataract burden from 2020 to 2034. RESULTS: Globally, the number of DALYs due to cataract increased from 3,492,604 (95% uncertainty interval [UI] 2,481,846-4,719,629) in 1990 to 6,676,281 (95% UI 4,761,210-9,006,193) in 2019. The ASDRs due to cataract decreased from 93.17 (95% UI 66.14-125.32) in 1990 to 82.94 (95% UI 59.06-111.75) in 2019, with an average annual percentage change of -0.37 (95% CI -0.44 to -0.3; P<.001). Age, female sex, air pollution, smoking, high fasting plasma glucose levels, and a high body mass index were risk factors for the burden of cataracts. SDI and HDI were negatively correlated with ASDRs of cataracts, while PM2.5 and UVR were positively associated with them. Higher DALY rates were also associated with lower SDI (R2=0.1939; P<.001), lower HDI (R2=0.2828; P<.001), national PM2.5 concentration (R2=0.1874; P<.001), and ambient UVR levels (R2=0.2354; P<.001). The prediction model suggested that the number of DALYs due to cataract will continue to rise globally, while the cataract DALY rate will continue to decrease. CONCLUSIONS: While the ASDR of cataracts has decreased, there has been a notable increase in the number of DALYs over the past 30 years. Projections suggest that the global burden of cataracts will continue to rise over the next 15 years. To address this challenge, appropriate prevention and treatment policies must be implemented.

Time trends and gender disparities of Chinese cataract burden and their predictions.

AIM: To evaluate the trends and changes in the number and rates of disability-adjusted life years (DALYs) and prevalence of cataract in China between 1990 and 2019, and to predict the trends of cataract burden from 2020 to 2030. METHODS: The Global Burden of Diseases (GBD) database was employed to collect the data on DALYs and the prevalence of cataract in China, which was distinguished by age and sex during the past three decades from 1990 to 2019, and then changes in the number and rates of cataract from 2020 to 2030 were predicted. All data were analyzed by the R program (version 4.2.2) and GraphPad Prism 9.0 statistics software. RESULTS: The number of DALYs of cataract increased from 449 322.84 in 1990 to 1 087 987.61 in 2019, number of cataract cases increased from 5 607 600.94 in 1990 to 18 142 568.96 in 2019. The age-standardized DALY rates (ASDR) generally increased slightly [estimated annual percentage change (EAPC=0.1; 95%CI: -0.24 to 0.45), age-standardized prevalence rates (ASPR) also increased (EAPC=0.88; 95%CI: 0.6 to 1.15). Cataract burden increased with age and female gender. Among the causes of cataract, air pollution was the most important, followed by smoking, high fasting plasma glucose, and high body mass index (BMI). The burden of cataract is predicted to grow persistently from 2020 to 2030, the number of DALYs and prevalence for cataract will rise to 2 336 431 and 43 698 620 respectively by 2030, the ASDR is predicted to be 85/100 000 and ASPR will be 1586/100 000 in 2030, females will still be at greater risk of suffering from cataract than males. CONCLUSION: The burden of cataract in China kept rising from 1990 to 2019. Increasing age and female gender are risk factors for cataract. Air pollution, smoking, high fasting plasma glucose, and high BMI are associated with cataract. The burden of cataract in China will gradually increase from 2020 to 2030, the elderly women in particular need attention. Our results may be of help for providing reference strategies to reduce cataract burden in the near future.

Efficacy and safety of ultrasound cycloplasty for the treatment of glaucoma: a Meta-analysis.

AIM: To evaluate the efficacy and safety of ultrasound cycloplasty (UCP) for glaucoma. METHODS: A comprehensive search of PubMed, Embase, Web of Science, and Google Scholar databases was used to select studies met the inclusion criteria. Meta-analysis was performed by Review Manager and StataCorp LLC. RESULTS: A total of 19 articles met the inclusion criteria. Overall, UCP is effective and safe in the glaucoma treatment, the risk ratio (RR) of the success rate was 2.28 (95%CI, 1.82-2.84). After UCP, patients had a significant reduction in intraocular pressure (IOP; mm Hg), the weighted mean difference (WMD) was 11.39 (95%CI, 9.88-12.90). In addition, UCP brings fewer postoperative complications with RR of 0.30 (95%CI, 0.19-0.49). Most of the complications were short-term and mild. Postoperatively, patients' use of IOP-lowering medications reduced, the standardized mean difference (SMD) was 0.78 (95%CI, 0.40-1.17). However, best corrected visual acuity (BCVA; logMAR) did not have obvious improvement after UCP, the WMD was 0.01 (95%CI, -0.06-0.09). This procedure does provide painfulness relief, with RR of 3.06 (95%CI, 1.95-4.81). CONCLUSION: UCP is effective and safe for suitable glaucoma. It can effectively decrease IOP in glaucoma patients, reduce the patients' dependence on IOP-lowering medications after surgery, relief the painfulness and has fewer long-term or severe postoperative complications, but the BCVA did not improve much.

Visualizing Drug Release from a Stimuli-Responsive Soft Material Based on Amine-Thiol Displacement.

In this research, we developed a photoluminescent platform using amine-coupled fluorophores, generated from a single conjugate acceptor containing bis-vinylogous thioesters. Based on the experimental and computational results, the fluorescence turn-on mechanism was proposed to be charge separated induced energy radiative transition for the amine-coupled fluorophore, while the sulfur-containing precursor was not fluorescent since the energy internal conversion occurred through vibrational 2RS- (R represents alkyl groups) as energy acceptor(s). Further utilizing the conjugate acceptor, we establish a new fluorogenic approach via a highly cross-linked soft material to selectively detect cysteine under neutral aqueous conditions. Turn-on fluorescence emission and macroscopic degradation occurred in the presence of cysteine as the stimuli, which can be visually tracked due to the generation of an optical indicator and the cleavage of linkers within the matrix. Furthermore, a novel drug delivery system was constructed, achieving controlled release of sulfhydryl drug (6-mercaptopurine) which was tracked by photoluminescence and high-performance liquid chromatography. The photoluminescent molecules developed herein are suitable for visualizing polymeric degradation, making them suitable for additional "smart" material applications.

"Indanonalkene" Photoluminescence Platform: Application in Real-Time Tracking the Synthesis, Remodeling, and Degradation of Soft Materials.

In this Article, we present a strategy to visually track chemically triggered covalent bonding processes in gelation, remodeling, and degradation of soft materials, i.e., hydrogels, based on a new photoluminescence platform. Initially in the development of photoluminophors named "indanonalkenes", turn-on emission can be tracked and quantified in the optical reaction between a conjugate acceptor and amine derivatives. On this basis, fluorescence enhancement and mechanical changes were recorded during the gelation process through amine-thiol exchanges under organic and aqueous conditions. Next in macromolecular remodeling, we realized a stimulus-induced transformation of one architecture into another one, exploiting the orthogonality of chemical covalent bonding that could be visualized using luminescence. Furthermore, the hydrogel network can be degraded to release the coupling partner induced by ethylene diamine, and the process can be monitored using fluorescence changes and quantified through gel permeation chromatography, while the released components can be utilized again to regenerate a new hydrogel. In addition, the photographic images provide alternatives to fluorescence spectra and can be digitally processed to quantify the macroscopic changes, resulting in a photographic imaging approach. The real-time observation and quantification of chemically triggered polymeric formation, morphology, and degradation through luminescence in spatial and time scales herald a new generation of "smart" materials.

A dual lock-and-key two photon fluorescence probe in response to hydrogen peroxide and viscosity: Application in cellular imaging and inflammation therapy.

Here, a dual lock-and-key fluorescence probe was developed for visualizing the inflammatory process in myocardial H9C2 cells. The probe possessed two-photon properties, viscosity sensitivity, and hydrogen peroxide (H2O2) responsiveness. A thiocarbamate spacer between fluorophore and H2O2 responsive unit enabled the release of carbonyl sulfide (COS). This rapidly converts to the anti-inflammatory hydrogen sulfide (H2S) by the ubiquitous enzyme carbon anhydrase. The probe displayed a dual response towards hydrogen peroxide and viscosity in vitro. No obvious fluorescence changes were observed towards either hydrogen peroxide or viscosity alone. In cellular experiments, the probe demonstrated good biocompatibility, low toxicity, and was shown responses towards exogenous and endogenous hydrogen peroxide under viscosity conditions. LPS induced cell inflammation showed it was able to effectively alleviate the inflammation-caused damage by releasing H2S and eliminating H2O2. The new protocol demonstrates its promising to achieve diagnosis and treatment of cellular inflammatory process.

Chemically Triggered Click and Declick Reactions: Application in Synthesis and Degradation of Thermosetting Plastics.

In this Letter, we report that two amines can be coupled together rapidly and quantitatively through amine-thiol scrambling using a bisvinylogous thioester conjugate acceptor under mild conditions. The resulting bisvinylogous amide conjugate acceptors can be decoupled via an ethylene diamine-induced cyclization. Four representative conjugate acceptors have been utilized in the couple-decouple reactions, which were monitored and characterized by nuclear magnetic resonance, high-resolution mass spectrometry, and UV-vis spectroscopy. Further, we applied these small-molecule-based "click-declick" reactions to polymer synthesis and degradation. Highly cross-linked polymers, i.e., plastics, were quantitatively synthesized by simple reactions between commercial tris(2-aminoethyl)amine and the conjugate acceptors without solvent and any initiator or catalyst through ball milling within 60 min. Significantly, these thermosetting plastics can be degraded within 3-24 h via addition of ethylene diamine. The multiple architectures, application to plastics synthesis, and chemically triggered clean degradation to the thermosets at mild conditions with little input of energy herald a new generation of "intelligent" materials.

Indicator displacement assays (IDAs): the past, present and future.

Indicator displacement assays (IDAs) offer a unique and innovative approach to molecular sensing. IDAs can facilitate the detection of a range of biologically/environmentally important species, provide a method for the detection of complex analytes or for the determination and discrimination of unknown sample mixtures. These attributes often cannot be achieved by traditional molecular sensors i.e. reaction-based sensors/chemosensors. The IDA pioneers Inouye, Shinkai, and Anslyn inspired researchers worldwide to develop various extensions of this idea. Since their early work, the field of indicator displacement assays has expanded to include: enantioselective indicator displacement assays (eIDAs), fluorescent indicator displacement assays (FIDAs), reaction-based indicator displacement assays (RIAs), DimerDye disassembly assays (DDAs), intramolecular indicator displacement assays (IIDAs), allosteric indicator displacement assay (AIDAs), mechanically controlled indicator displacement assays (MC-IDAs), and quencher displacement assays (QDAs). The simplicity of these IDAs, coupled with low cost, high sensitivity, and ability to carry out high-throughput automation analysis (i.e., sensing arrays) has led to their ubiquitous use in molecular sensing, alongside the other common approaches such as reaction-based sensors and chemosensors. In this review, we highlight the various design strategies that have been used to develop an IDA, including the design strategies for the newly reported extensions to these systems. To achieve this, we have divided this review into sections based on the target analyte, the importance of each analyte and then the reported IDA system is discussed. In addition, each section includes details on the benefit of the IDAs and perceived limitations for each system. We conclude this Tutorial Review by highlighting the current challenges associated with the development of new IDAs and suggest potential future avenues of research.

A Simple 3D-Printed Enzyme Reactor Paper Spray Mass Spectrometry Platform for Detecting BuChE Activity in Human Serum.

To achieve personalized healthcare, a quick, accurate, and high-throughput method to detect disease biomarkers is essential. In the traditional practice, mass spectrometry is one of the most powerful tools and is widely studied. However, the test of human serum usually requires complicated sample pretreatment, tedious operations, and precise condition control, especially for the detection of enzymes as biomarkers. As butyrylcholinesterase (BuChE) has an indicative significance in detecting degenerative disease, liver injury, and organophosphate poisoning, the quick quantification of BuChE is of vital importance to the clinic. In this paper, we report the design and fabrication of a portable 3D-printed enzyme reactor paper spray cartridge (3D ER-PS) with integrated functions: temperature control, enzyme reaction, analyte transfer, and paper spray ionization. Coupled with mass spectrometry, quantitative testing of BuChE activity in human serum was realized conveniently and accurately. While it only requires very simple sample preparation, the results from current 3D ER-PS approach are well consistent with those obtained using Ellman's method. This 3D ER-PS platform not only provides a novel solution for the liquid biopsy of BuChE in clinics but also contributes to the development of quick and targeted medical approaches for analyzing other types of serum biomarker molecules in the field of disease diagnosis.

A two-photon fluorescent probe for ratiometric visualization of hypochlorous acid in live cells and animals based on a selenide oxidation/elimination tandem reaction.

Utilizing the oxidation/elimination tandem reaction of the α-phenylseleno carbonyl moiety, a two-photon fluorescent probe for ratiometric visualization of hypochlorous acid was developed. Its superior sensing performance and practical applications were well demonstrated.

Rational Design of an α-Ketoamide-Based Near-Infrared Fluorescent Probe Specific for Hydrogen Peroxide in Living Systems.

Hydrogen peroxide, an important biomolecule, receives earnest attention because of its physiological and pathological functions. In this Article, we present the rational design, characterization, and biological application of a mitochondria-targetable NIR fluorescent sensor, Mito-NIRHP, for hydrogen peroxide visualization. Mito-NIRHP utilizes a unique reaction switch, α-ketoamide moiety, to turn on a highly specific, sensitive, and rapid fluorescence response toward hydrogen peroxide coupled with the intramolecular charge transfer strategy. Mito-NIRHP is competent to track endogenously produced hydrogen peroxide in both living cells and living animals. In addition, utilizing Mito-NIRHP, overgeneration of hydrogen peroxide during ischemia-reperfusion injury was directly visualized at both cell and organ levels.