A Hypochlorite-Activated Theranostic Prodrug for Selective Imaging of High Myeloperoxidase Expression Acute Myeloid Leukemia Cells and Drug Release.

Acute myeloid leukemia (AML) is a fatal hematologic disease. Diagnosis and proper treatment are important for prognosis. High myeloperoxidase (MPO) expression AML cells are characterized with high levels of hypochlorite (ClO-). In this study, we report a ClO--activated theranostic agent, FNC, for AML therapy. FNC responds to ClO- specifically in high MPO expression AML cells, resulting in bright fluorescence and chlorambucil release. FNC can be used to quickly distinguish high MPO expression AML cells from other cells, including low MPO expression leukemia and activated inflammatory cells. FNC exhibits selective toxicity to highly MPO expression AML cells and can efficiently inhibit tumor growth. Meanwhile, FNC can be used to indicate differentiation through the detection of ClO-.

The systemic inflammation response index as a risk factor for hepatic fibrosis and long-term mortality among individuals with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: The systemic inflammation response index (SIRI) is associated with various diseases with inflammatory components, but its relationship with the progression of hepatic fibrosis and survival outcomes in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is still unclear. This study was designed to investigate the potential associations between the SIRI and advanced hepatic fibrosis (AHF) as well as between the SIRI and long-term outcomes in individuals with MASLD. METHODS AND RESULTS: A prospective cohort study was conducted using data gathered from the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2016. Weighted binary logistic regression, the Cox proportional hazards model, and time-dependent receiver operating characteristic (ROC) analyses were employed to assess the relationships among the SIRI, AHF, and mortality in patients with MASLD. Our study included a total of 5126 patients with MASLD. A higher SIRI was significantly associated with increased odds of AHF (OR 1.55, 95% CI 1.22, 1.96). According to the survival analyses, a higher SIRI was associated with greater all-cause (HR 1.19, 95% CI 1.15, 1.22) and cardiovascular mortality (HR 1.25, 95% CI 1.19, 1.32) after adjustment. The time-dependent ROC analysis indicated that the SIRI had a modest predictive value for discriminating MASLD individuals at higher versus lower mortality risk over 3-year, 5-year, and 10-year follow-up. CONCLUSIONS: The SIRI is a promising tool for identifying MASLD individuals at risk of progressing to AHF and for predicting mortality outcomes.

Target-Binding Accelerated Response for Sensitive Detection of Basal H2O2 in Tumor Cells and Tissues via a Dual-Functional Fluorescence Probe.

Aberrant production of H2O2 is involved in cancer. The levels of H2O2 are significantly higher in tumor cells than in normal cells. It is important to develop fluorescent probes to image basal H2O2 selectively in tumor cells. So far, a cancer cell-targeting probe to image basal H2O2 has not been reported. Thus, we developed a fluorescent probe, BBHP, which contains benzil as a H2O2-recognition site and biotin as a target binding motif for the selective and sufficient detection of H2O2 in tumor cells. BBHP enables a selective fluorescence turn-on response to H2O2. The binding of the probe with biotin receptors can greatly accelerate the fluorescence response to H2O2. As a result, BBHP can sufficiently image basal H2O2 in biotin receptor-positive cancer cells and tumor tissues. Finally, BBHP was successfully applied to discriminate between cancerous and normal tissues.

Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury.

Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid ß-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.

A simple method for the preparation of CeO2with high antioxidant activity and wide application range.

Cerium oxide (CeO2) is a well-known antioxidant with the ability to scavenge reactive oxygen species due to its unique electronic structure and chemical properties. Although many methods to enhance the antioxidant activity of CeO2have been reported, its antioxidant activity is still not high enough, and some enhancement effects are limited by the material concentration. There are also some CeO2obtained with high antioxidant activity at high concentrations, which is not conducive to the application of biomedicine. Therefore, it is urgent to obtain CeO2material with low cell cytotoxicity, high antioxidant activity and wide application range. In this work, rod-like metal organic framework derived CeO2(CeO2-MOF) was prepared by a simple method. Compared with the CeO2nanorods prepared by hydrothermal method, it shows better antioxidant activity compared with the CeO2nanorods prepared by hydrothermal method. Moreover, the advantage of CeO2-MOF's antioxidant activity is not affected by the hydroxyl radical and material concentrations The reason why CeO2-MOF has higher antioxidant activity should be attributed to its higher Ce3+content and larger specific surface area. In addition, CeO2-MOF also exhibits low cytotoxicity to HeLa cells and PC12 cellsin vitro. The strategy of using MOF as a structural and compositional material to create CeO2provides a new method to explore highly efficient and biocompatible CeO2for practical applications.

Copper/Carbon Heterogenous Interfaces for Enhanced Selective Electrocatalytic Reduction of CO2 to Formate.

Electrochemical reduction of CO2 (CO2 RR) to formate is a promising route to prepare value-added chemical. Developing low-cost and efficient electrocatalysts with high product selectivity is still a grand challenge. Herein, a novel Cu anchored on hollow carbon spheres catalysts (HCS/Cu-x, x represents the mass of CuCl2 added in the system) is designed with controllable copper/carbon heterogenous interfaces. Rich copper/carbon heterogenous interfaces and hollow structure of optimized HCS/Cu-0.12 catalyst are beneficial to charge transmission. Compared with the CO2 RR occurred in aqueous electrolyte over Cu-based catalyst that has been reported to date, it exhibits highest formate Faradaic efficiency (FE) of 82.4% with a current density of 26 mA cm-2 and remarkable stability in a H-cell.

Analysis of clinical characteristics and genetic testing in patients with acute fatty liver of pregnancy: a retrospective study.

BACKGROUND: Acute fatty liver of pregnancy (AFLP) is an acute, rare and potentially lethal disease typically occurring in the third trimester of pregnancy. So far, there is no effective means of prevention. Therefore, in this study, we retrospectively analyzed the clinical features of AFLP patients for a better understanding. Meanwhile, for the first time, the genetic background associated with the onset of AFLP was discussed by high-throughput sequencing, hoping to provide evidence for genetic counseling and prenatal diagnosis of AFLP. METHODS: Thirteen AFLP patients admitted to our hospital and other hospital from March 2012 to February 2020 were selected. Clinical data about general condition, laboratory test, liver biopsy and the prognosis of mother and fetus were collected for retrospective analysis. In addition, the peripheral blood of five patients with AFLP and one newborn infant of his mother with AFLP was sequenced with whole-exome sequencing and gene mutation was analyzed by bioinformatics methods. RESULTS: The initial symptoms of AFLP varied differently, with jaundice (9/13, 69%), fatigue (8/13, 62%) and nausea and vomiting (6/13, 46%) being the most common. Moreover, the main maternal complications were coagulopathy (13/13, 100%), followed by acute renal dysfunction (10/13, 77%). Raised serum bilirubin, transaminases and uric acid were found in all patients (100%), hypoglycemia was found in six patients (46%) and fatty liver on ultrasound was seen in five patients (5/12, 42%). One (7%) maternal death occurred and all neonates survived delivery. In addition, to our surprise, whole-exome sequencing showed that no gene mutation in related enzymes involved in fatty acid metabolism was noted in the pregnant women and children receiving genetic testing. CONCLUSIONS: Early visit, early detection, early termination of pregnancy and multidisciplinary comprehensive treatment are the key factors to improve the prognosis of AFLP patients and their newborn infants. Furthermore, although limited size of study, to our knowledge, this report is the first to present the lack of common mutation involved in fatty acid oxidation in Chinese patients with AFLP via whole-exome sequencing. Thus, further studies are needed with larger and more varied samples to validate the conclusion.

Design Principles, Sensing Mechanisms, and Applications of Highly Specific Fluorescent Probes for HOCl/OCl.

Hypochlorous acid/hypochlorite (HOCl/OCl-), one of the most important reactive oxygen species (ROS), plays vital roles in various physiological and pathological processes. At normal concentrations, OCl- acts as part of an immune defense system by destroying invasive bacteria and pathogens. However, nonproperly located or excessive amounts of OCl- are related to many diseases, including cancers. Thus, detection of OCl- has great importance. Owing to their high sensitivities, selectivities, fast response times, technical simplicities, and high temporal and spatial resolution, fluorescent probes are powerful tools for in vitro and in vivo sensing of target substances. This Account focuses on the development of new chemosensors for detection of OCl-, which operate by undergoing a chemical reaction with this ROS in conjunction with a change in emission properties. As part of the presentation, we first introduce several important factors that need to be considered in the design of fluorescent chemosensors for OCl-, including fluorophores, reaction groups, cosolvents, and buffers. Discussion here revolves around the need to select fluorophores that resist oxidation by OCl-. As well, attention is given to the sensitivities and selectivities of groups in the sensors that react with OCl- to trigger a fluorescence response. Moreover, well-known reaction groups, which react with highly reactive ROS (hROS), have been redesigned to be specific for OCl-. In addition, it is pointed out that several cosolvents and buffers such as DMSO and HEPES are not suitable for use in systems for the detection of OCl- because they are readily oxidized by this ROS. We further discuss recent investigations carried out by us and others aimed at the development of fluorescent probes for in vitro and in vivo detection of OCl-. These efforts led to the new "dual lock" strategy for designing OCl- chemosensors as well as several new specific reaction groups such as imidazoline-2-thiones and imidazoline-2-boranes. Probes created using this strategy and the new reacting groups have been successfully applied to imaging exogenous and endogenous OCl- in live cells and/or tissues. The design concepts and strategies emanating from our studies of fluorescent OCl- probes have provided insight into the general field of fluorescent probes. Despite the progress made thus far, challenges still remain in developing and applying fluorescent OCl- probes. For example, more highly specific and sensitive fluorescent OCl- probes are still in great demand for studies of the biological roles played by OCl-. Thus, interdisciplinary collaborations of chemists, biologists, and medical practitioners are needed to drive future developments of OCl- probes for disease diagnosis and drug screening.

Development of A Thermo-Responsive Conjugated Polymer with Photobleaching-Resistance Property and Tunable Photosensitizing Performance.

A thermo-responsive conjugated polymer, PFBT-gPA is synthesized by grafting the poly(N-isopropylacrylamide) (PNIPAAm) to the side chains of a conjugated polyfluorene derivative through atom transfer radical polymerization (ATRP). PFBT-gPA undergoes a reversible phase transition in water below and above the lower critical solution temperature (LCST) and the process is studied by differential scanning calorimetry (DSC) analysis and UV/vis absorption spectra. PFBT-gPA shows a good photostability under UV light irradiation especially above the LCST. Moreover, the photosensitizing performance of PFBT-gPA could be tuned simply by changing temperature. The unique properties of PFBT-gPA promise its potential applications in sensing and photodynamic therapy.

GADD45α alleviates acetaminophen-induced hepatotoxicity by promoting AMPK activation.

As an analgesic and antipyretic drug, acetaminophen (APAP) is commonly used and known to be safe at therapeutic doses. In many countries, the overuse of APAP provokes acute liver injury and even liver failure. APAP-induced liver injury (AILI) is the most used experimental model of drug-induced liver injury (DILI). Here, we have demonstrated elevated levels of growth arrest and DNA damage-inducible 45α (GADD45α) in the livers of patients with DILI/AILI, in APAP-injured mouse livers and in APAP-treated hepatocytes. GADD45α exhibited a protective effect against APAP-induced liver injury and alleviated the accumulation of small lipid droplets in vitro and in vivo. We found that GADD45α promoted the activation of AMP-activated protein kinase α and induced fatty acid beta-oxidation, tricarboxylic acid cycle (TCA) and glycogenolysis-related gene expression after APAP exposure. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that GADD45α increased the levels of TCA cycle metabolites. Co-immunoprecipitation analysis showed that Ppp2cb, a catalytic subunit of protein phosphatase 2A, could interact directly with GADD45α. Our results indicate that hepatocyte GADD45α might represent a therapeutic target to prevent and rescue liver injury caused by APAP.

Telbivudine can safely reduce mother-to-child transmission in chronic hepatitis B women after 12 weeks of gestation.

BACKGROUND: To evaluate the efficacy and safety of telbivudine in chronic hepatitis B women during the second and third trimesters of pregnancy. METHODS: The week 12-34 of pregnant women were screened in this prospective non-intervention study, with HBV DNA > 106 IU/mL and alanine aminotransferase > 50 IU/L. The patients were received telbivudine treatment as a treatment group or without antiviral treatment as a control group. All infants were received recombinant hepatitis B vaccine 10 µg within 12 h of birth, at week 4 and week 24, immunoglobulin G within 12 h of birth and were detected HBV markers at the range from 7 to 12 months after delivery. RESULTS: A total of 241 patients were finally enrolled, 139 patients in telbivudine group and 102 patients in control group. HBsAg negative rate of infants was 99.3% (135/136) in telbivudine group and was 91.9% (91/99) in control group after 7 months (P = 0.005), respectively. The incidence of undetectable HBV DNA levels (47.5%) was significantly lower in telbivudine-treated mothers than that in the controls (0%), and 75.5% patients alanine aminotransferase returned to normal in telbivudine group, and 51% in control group at delivery (P < 0.001), respectively. CONCLUSIONS: Telbivudine can safely reduce mother-to-child transmission in chronic hepatitis B women after 12 weeks of gestation.

Ratiometric Two-Photon Fluorescent Probe for Detecting and Imaging Hypochlorite.

The ratiometric fluorescent probe B6S, which contains pyrene as a fluorophore and imidazoline-2-thione as a reactive site, was developed for detection of hypochlorite (OCl-). B6S displays a high specificity toward OCl- in contrast to other reactive oxygen species and reactive nitrogen species. The probe has a low detection limit and operates under biological conditions. Moreover, the low cytotoxicity of B6S enables it to be utilized effectively for OCl- imaging in living cells and tissues by using two-photon microscopy. The findings indicate that B6S has the capability of serving as a probe to explore the biological functions of OCl- in living systems.

A Selective Imidazoline-2-thione-Bearing Two-Photon Fluorescent Probe for Hypochlorous Acid in Mitochondria.

Hypochlorite (OCl(-)) plays a key role in the immune system and is involved in various diseases. Accordingly, direct detection of endogenous OCl(-) at the subcellular level is important for understanding inflammation and cellular apoptosis. In the current study, a two-photon fluorescent off/on probe (PNIS) bearing imidazoline-2-thione as an OCl(-) recognition unit and triphenylphosphine (TPP) as a mitochondrial-targeting group was synthesized and examined for its ability to image mitochondrial OCl(-) in situ. This probe, based on the specific reaction between imidazoline-2-thione and OCl(-), displayed a selective fluorescent off/on response to OCl(-) with the various reactive oxygen species in a physiological medium. PNIS was successfully applied to image of endogenously produced mitochondrial OCl(-) in live RAW 264.7 cells via two-photon microscopy.

Development of imidazoline-2-thiones based two-photon fluorescence probes for imaging hypochlorite generation in a co-culture system.

We designed and prepared the imidazoline-2-thione containing OCl(-) probes, PIS and NIS, which operate through specific reactions with OCl(-) that yield corresponding fluorescent imidazolium ions. Importantly, we demonstrated that PIS can be employed to image OCl(-) generation in macrophages in a co-culture system. We have also employed two-photon microscopy and PIS to image OCl(-) in live cells and tissues, indicating that this probe could have wide biological applications.

A selective mitochondria-targeted fluorescent probe for imaging cysteine in drug-induced liver injury.

Cysteine (Cys) is involved in many physiological processes. It's challenging to detect Cys selectively as it has similar chemical structure with other biothiols such as homocysteine (Hcy) and glutathione (GSH). In this work, a novel fluorescence probe toward mitochondrial cysteine, HPXI-6C, has been developed by employing carbonate as a new recognizing unit and hemicyanine as a chromophore. HPXI-6C exhibits a high selectivity to Cys over hydrogen sulfide, homocysteine and glutathione. The limit of detection toward Cys was determined to be 42 nM. HPXI-6C can localize in mitochondria and produce strong fluorescence peaked at 725 nm in response to Cys in tumor cells. The uptake and generation pathways of Cys in acetaminophen hepatotoxicity cells was revealed by using HPXI-6C. HPXI-6C has been successfully applied in imaging of Cys in drug-induced liver injury in vivo. The research demonstrated that HPXI-6C is powerful in monitoring Cys and is conducive to the early diagnosis of drug-induced liver injury diseases.

Modified EBP-bFGF targeting endogenous renal extracellular matrix protects against renal ischemia-reperfusion injury in rats.

Acute kidney injury (AKI) is a life-threatening disease primarily caused by renal ischemia-reperfusion (I/R) injury, which can result in renal failure. Currently, growth factor therapy is considered a promising and effective approach for AKI treatment. Basic fibroblast growth factor (bFGF), an angiogenic factor with potent activity, efficiently stimulates angiogenesis and facilitates regeneration of renal tissue. However, the unrestricted diffusion of bFGF restricts its clinical application in AKI treatment. Therefore, developing a novel sustained released system for bFGF could enhance its potential in treating AKI. In this study, we genetically engineered a multifunctional recombinant protein by fusing bFGF with a specific peptide (EBP). EBP-bFGF effectively binds to the extracellular matrix in the injured kidney, enabling slow release of bFGF in AKI. Furthermore, following orthotopic injection into I/R rats' ischemic kidneys, EBP-bFGF exhibited stable retention within the tissue. Additionally, EBP-bFGF suppressed apoptosis of renal cells, reduced renal fibrosis, and facilitated recovery of renal function. These findings suggest that EBP-bFGF delivery system represents a promising strategy for treating AKI.

Ambient-pressure alkoxycarbonylation for sustainable synthesis of ester.

Alkoxycarbonylation reactions are common in the chemical industry, yet process sustainability is limited by the inefficient utilization of CO. In this study, we address this issue and demonstrate that significant improvements can be achieved by adopting a heterogeneously catalyzed process, using a Ru/NbOx catalyst. The Ru/NbOx catalyst enables the direct synthesis of methyl propionate, a key industrial commodity, with over 98% selectivity from CO, ethylene and methanol, without any ligands or acid/base promoters. Under ambient CO pressure, a high CO utilization efficiency (336 mmolestermolCO-1h-1) is achieved. Mechanistic investigations reveal that CO undergoes a methoxycarbonyl (COOCH3) intermediate pathway, attacking the terminal carbon atom of alkene and yielding linear esters. The origins of prevailing linear regioselectivity in esters are revealed. The infrared spectroscopic feature of the key COOCH3 species is observed at 1750 cm-1 (C=O vibration) both experimentally and computationally. The broad substrate applicability of Ru/NbOx catalyst for ester production is demonstrated. This process offers a sustainable and efficient approach with high CO utilization and atom economy for the synthesis of esters.

Polydiacetylene-based colorimetric and fluorescent chemosensor for the detection of carbon dioxide.

We developed a colorimetric and fluorescent turn-on carbon dioxide sensor that relies on a polydiacetylene, PDA-1, functionalized with amines and imidazolium groups. The pendant amines react with CO2 under basic conditions to form carbamoate anions, which partially neutralize the polymer's positive charges, inducing a phase transition. PDA-1 allows for the selective sensing of CO2 with high sensitivity, down to atmospheric concentrations. Naked-eye detection of CO2 is accomplished either in water solutions of PDA-1 or in the solid state with electrospun coatings of PDA-1 nanofibers.

A highly specific fluorescent probe for hypochlorous acid and its application in imaging microbe-induced HOCl production.

Oxidative stress induced by reactive oxygen species (ROS) plays crucial roles in a wide range of physiological processes and is also implicated in various diseases, including cancer, chronic inflammatory diseases, and neurodegenerative disorders. Among the various ROS, hypochlorous acid (HOCl) plays as a powerful microbicidal agent in the innate immune system. The regulated production of microbicidal HOCl is required for the host to control the invading microbes. However, as a result of the highly reactive and diffusible nature of HOCl, its uncontrolled production may lead to an adverse effect on host physiology. Because of its biological importance, many efforts have been focused on developing selective fluorescent probes to image ROS. However, it is still challenging to design a fluorescent probe with exclusive selectivity toward a particular member of ROS. In the current work, we designed FBS as a new fluorescent HOCl probe which has high selectivity, sensitivity, and short response time in a broad range of pH. Compared with other sensors, the "dual-lock" structure of FBS has an advantage of eliminating interferences from other ROS/RNS. Importantly, we further showed that our HOCl probe could be applied for the in vivo imaging of physiological HOCl production in the mucosa of live animals. This probe provides a promising tool for the study of HOCl production.

Risk of herpes zoster associated with JAK inhibitors in immune-mediated inflammatory diseases: a systematic review and network meta-analysis.

Objective: Janus kinase (JAK) inhibitors are a novel class of drugs that have shown efficacy in treating immune-mediated inflammatory diseases (IMIDs). However, their safety profile in terms of herpes zoster infection remains unclear. We aimed to evaluate the risk of herpes zoster associated with JAK inhibitors in patients with IMIDs. Methods: A systematic search of electronic databases was conducted to identify randomized controlled trials (RCTs) that evaluated the safety of JAK inhibitors in patients with IMIDs including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriasis (PsO), and psoriatic arthritis (PsA). The primary outcome of interest was the incidence of herpes zoster infection. Network meta-analysis was performed to compare the risk of herpes zoster among different JAK inhibitors and placebo. Results: A network meta-analysis was conducted using data from 47 RCTs including 24,142 patients. In patients with IMIDs, peficitinib 100 mg QD was associated with the highest risk of herpes zoster infection in patients with IMIDs, followed by baricitinib 4 mg QD and upadacitinib 30 mg QD. No difference in herpes zoster risk was found for other JAK inhibitors compared with placebo. Subgroup analysis indicated that higher incidence of herpes zoster was found in patients treated by baricitinib 4 mg QD, peficitinib 100 mg QD, and upadacitinib 30 mg QD only in patients with RA. Conclusion: Our study suggests that some JAK inhibitors, particularly peficitinib, baricitinib, and tofacitinib, are associated with a higher risk of herpes zoster infection in patients with IMIDs.