Subsurface Single-atom Catalyst Enabled by Mechanochemical Synthesis for Oxidation Chemistry.

Single-atom catalysts have garnered significant attention due to their exceptional atom utilization and unique properties. However, the practical application of these catalysts is often impeded by challenges such as sintering-induced instability and poisoning of isolated atoms due to strong gas adsorption. In this study, we employed the mechanochemical method to insert single Cu atoms into the subsurface of Fe2O3 support. By manipulating the location of single atoms at the surface or subsurface, catalysts with distinct adsorption properties and reaction mechanisms can be achieved. It was observed that the subsurface Cu single atoms in Fe2O3 remained isolated under both oxidation and reduction environments, whereas surface Cu single atoms on Fe2O3 experienced sintering under reduction conditions. The unique properties of these subsurface single-atom catalysts call for innovations and new understandings in catalyst design.

Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 µM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

Epicardial fat modifies the relationship between coronary calcium score and all-cause mortality: The St. Francis Heart Study.

Objective: Epicardial fat is associated with cardiovascular risk factors and adverse outcomes. However, it is not clear if epicardial fat remains to be a mortality risk when coronary calcium score (CAC) is taken into account. Methods: We studied the 1005 participants from the St. Francis Heart Study who were apparently healthy with CAC scores at 80th percentile or higher for age and gender, randomly assigned to placebo or statin therapy. At baseline, lipid profiles and non-contrast CT images were obtained where the epicardial fat volume was analyzed. Likelihood ratio testing was used to assess the additional prognostic value of epicardial fat to CAC for the risk of all-cause mortality. Results: Increased epicardial fat volume was associated with higher CAC. For each unit increase in lnCAC, the average epicardial fat volume increased by 3.34 mL/m2. After a mean follow-up period of 17 years, 179 (18%) participants died. Increased epicardial fat volume was associated with an adjusted hazard ratio of 1.11 (95% CI: 1.02 to 1.20) predicting all-cause mortality. In the stratified analysis testing strata of epicardial fat and CAC, those with increased epicardial fat and increased CAC had the highest risk of death. Compared with a model containing lnCAC and traditional risk factors, a model additionally containing epicardial fat volume yielded a better model fit (likelihood ratio test p < 0.001). Conclusion: Increased epicardial fat volume is associated with increased all-cause mortality risk. In addition, it portends incremental prognostic value to CAC score in mortality prediction.

Metabolism score and machine learning models for the prediction of esophageal squamous cell carcinoma progression.

The incomplete prediction of prognosis in esophageal squamous cell carcinoma (ESCC) patients is attributed to various therapeutic interventions and complex prognostic factors. Consequently, there is a pressing demand for enhanced predictive biomarkers that can facilitate clinical management and treatment decisions. This study recruited 491 ESCC patients who underwent surgical treatment at Huashan Hospital, Fudan University. We incorporated 14 blood metabolic indicators and identified independent prognostic indicators for overall survival through univariate and multivariate analyses. Subsequently, a metabolism score formula was established based on the biochemical markers. We constructed a nomogram and machine learning models utilizing the metabolism score and clinically significant prognostic features, followed by an evaluation of their predictive accuracy and performance. We identified alkaline phosphatase, free fatty acids, homocysteine, lactate dehydrogenase, and triglycerides as independent prognostic indicators for ESCC. Subsequently, based on these five indicators, we established a metabolism score that serves as an independent prognostic factor in ESCC patients. By utilizing this metabolism score in conjunction with clinical features, a nomogram can precisely predict the prognosis of ESCC patients, achieving an area under the curve (AUC) of 0.89. The random forest (RF) model showed superior predictive ability (AUC = 0.90, accuracy = 86%, Matthews correlation coefficient = 0.55). Finally, we used an RF model with optimal performance to establish an online predictive tool. The metabolism score developed in this study serves as an independent prognostic indicator for ESCC patients.

Repurposing cyclovirobuxine D as a novel inhibitor of colorectal cancer progression via modulating the CCT3/YAP axis.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) ranks second in mortality worldwide and requires effective and affordable remedies. Cyclovirobuxine D (CVB-D) is the main effective component of Huangyangning tablet, an approved traditional patent medicine, which is mainly used for cardiovascular treatment. As a multibioactive natural compound, CVB-D possesses underlying anticancer activities. EXPERIMENTAL APPROACH: Cell viability and clone-forming ability were determined in human CRC lines. Western blot, immunofluorescence assay, transmission electron microscopy and senescence-associated ß-galactosidase (SA-ß-Gal) staining were utilized to investigate cell autophagy and senescence. The molecular mechanisms were explored by virtual prediction and experimental validation. Patient-derived xenograft (PDX), dextran sulfate sodium salt (DSS), and azomethane (AOM)/DSS mouse models were employed for in vivo studies. KEY RESULTS: CVB-D inhibited the growth and development of advanced CRC cells / mice by inducing autophagic and senescent activities through the chaperonin containing TCP1 subunit 3 (CCT3)/yes-associated protein (YAP) axis. CVB-D acted as a promising inhibitor of CCT3 by interacting with its ATP site. In PDX tumours, CVB-D showed potential therapeutic effects by targeting CCT3. Treatment with CVB-D alleviated the mouse model of colitis induced by DSS and attenuated AOM/DSS-induced formation of adenomatous polyps by its action on CCT3. CONCLUSIONS AND IMPLICATIONS: Our study has provided a scientific basis for the suggestion that CVB-D may be recognized as a prospective drug candidate for the therapy of CRC in patients.

Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.

OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS. METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation. RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972. CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.

Construction and validation of a nomogram for blood transfusion after open reduction and internal fixation (ORIF) of proximal humeral fractures in the elderly: a cross-sectional study.

PURPOSE: Few studies have focused on the risk factors leading to postoperative blood transfusion after open reduction and internal fixation (ORIF) of proximal humeral fractures (PHFs) in the elderly. Therefore, we designed this study to explore potential risk factors of blood transfusion after ORIF for PHFs. We have also established a nomogram model to integrate and quantify our research results and give feedback. METHODS: In this study, we retrospectively analyzed the clinical data of elderly PHF patients undergoing ORIF from January 2020 to December 2021. We have established a multivariate regression model and nomograph. The prediction performance and consistency of the model were evaluated by the consistency coefficient and calibration curve, respectively. RESULTS: 162 patients met our inclusion criteria and were included in the final study. The following factors are related to the increased risk of transfusion after ORIF: time to surgery, fibrinogen levels, intraoperative blood loss, and surgical duration. CONCLUSIONS: Our patient-specific transfusion risk calculator uses a robust multivariable model to predict transfusion risk.The resulting nomogram can be used as a screening tool to identify patients with high transfusion risk and provide necessary interventions for these patients (such as preoperative red blood cell mobilization, intraoperative autologous blood transfusion, etc.).

Waveform Design for the Integrated Sensing, Communication, and Simultaneous Wireless Information and Power Transfer System.

Next-generation communication systems demand the integration of sensing, communication, and power transfer (PT) capabilities, requiring high spectral efficiency, energy efficiency, and low cost while also necessitating robustness in high-speed scenarios. Integrated sensing and communication systems (ISACSs) exhibit the ability to simultaneously perform communication and sensing tasks using a single RF signal, while simultaneous wireless information and power transfer (SWIPT) systems can handle simultaneous information and energy transmission, and orthogonal time frequency space (OTFS) signals are adept at handling high Doppler scenarios. Combining the advantages of these three technologies, a novel cyclic prefix (CP) OTFS-based integrated simultaneous wireless sensing, communication, and power transfer system (ISWSCPTS) framework is proposed in this work. Within the ISWSCPTS, the CP-OTFS matched filter (MF)-based target detection and parameter estimation (MF-TDaPE) algorithm is proposed to endow the system with sensing capabilities. To enhance the system's sensing capability, a waveform design algorithm based on CP-OTFS ambiguity function shaping (AFS) is proposed, which is solved by an iterative method. Furthermore, to maximize the system's sensing performance under communication and PT quality of service (QoS) constraints, a semidefinite relaxation (SDR) beamforming design (SDR-BD) algorithm is proposed, which is solved using through the SDR technique. The simulation results demonstrate that the ISWSCPTS exhibits stronger parameter estimation performance in high-speed scenarios compared to orthogonal frequency division multiplexing (OFDM), the waveform designed by CP-OTFS AFS demonstrates superior interference resilience, and the beamforming designed by SDR-BD strikes a balance in the overall performance of the ISWSCPTS.

Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Reliability and validity study of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale in patients with cerebellar injury.

PURPOSE: To preliminarily investigate the reliability and validity of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale (CCAS scale) in the cerebellar injury population. METHODS: In this study, 40 patients with cerebellar injury and 39 normal individuals hospitalized in a stroke center were assessed using the Chinese version of the CCAS scale A, MMSE, and PHQ2, and the results were analyzed using content validity, structural validity, internal consistency, inter- rater agreement, and test-retest reliability. RESULTS: The correlation coefficients of semantic fluency, phonemic fluency, category switching, digit span forward, digit span backward, cube, verbal recall, similarities and Go No-Go subscores in the Chinese version of the CCAS scale A were 0.586-0.831 (P ≤ 0.05) with the total score, but there was no significant correlation between the affect and the total score (P = 0.110). The total cognitive score of the Chinese version of the CCAS scale A was correlated with the (r = 0.807, P ≤ 0.01), and the total score of the Chinese version of the CCAS scale A affect was correlated with the total score of PHQ2 (r = 0.884, P ≤ 0.01). The 2 factors were extracted using principal component analysis, and the cumulative variance contribution rate was 59.633%. The factor loadings of each of the corresponding factors were > 0.5, indicating good structural validity of the Chinese version of the CCAS scale A. Cronbach α = 0.827 indicated good internal consistency, and inter-rater reliability (ICC > 0.95) and test-retest reliability (ICC = 0.717-0.895)indicated that the Chinese version of the CCAS scale A had good inter-rater reliability and test-retest reliability. CONCLUSION: The Chinese version of the CCAS scale A has good reliability and validity in the cerebellar injury population and is useful for screening cerebellar cognitive-emotional syndrome.

3D-printed bone regeneration scaffolds modulate bone metabolic homeostasis through vascularization for osteoporotic bone defects.

The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed "vascularization-bone metabolic balance". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into "H"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects.

Specific immunological characteristics and risk factor of XBB variants re-infection in nasopharyngeal carcinoma patients after BA.5 infection.

OBJECTIVES: The specific humoral immune response resulting from inactivated vaccination following by BA.5 infection, and predictors of XBB variants re-infection in BA.5 infection-recovered nasopharyngeal carcinoma (BA.5-RNPC) patients, were explored. METHODS: Serum SARS-CoV-2 specific antibody levels were assessed using enzyme-linked-immunosorbent-assay. Univariate and multivariate binary logistic regression analyses were conducted to identify factors associated with the magnitude of specific humoral immunity and susceptibility to re-infection by XBB variants. RESULTS: Our data demonstrates that SARS-CoV-2 specific antibody levels were comparable between BA.5-RNPC patients and BA.5 infection-recovered-non-cancerous (BA.5-RNC) individuals. Specifically, serum levels of anti-ancestral-S1-IgG, anti-ancestral-nucleocapsid-protein (NP)-IgG, anti-BA.5-receptor binding domain (RBD)-IgG and anti-XBB.1.1.6-RBD-IgG were higher in BA.5-RNPC patients compared to those without a prior infection. Compared to BA.5-RNPC patients without vaccination, individuals who received inactivated vaccination exhibited significantly higher levels of anti-ancestral-S1-IgG and anti-XBB.1.16-RBD-IgG. Multivariate logistic regression analysis revealed that inactivated vaccination was the most significant predictor of all tested SARS-CoV-2 specific antibodies response. Subsequent analysis indicated that a low globulin level is an independent risk factor for XBB re-infection in BA.5-RNPC patients. CONCLUSIONS: The SARS-CoV-2 specific antibodies have been improved in vaccinated BA.5-RNPC patients. However, the baseline immunity status biomarker IgG is an indicators of XBB variant re-infection risk in BA.5-RNPC patients.

Determination of eleven components in rat plasma by UPLC-MS/MS and GC-MS for pharmacokinetic studies after oral administration of Citri Reticulatae Pericarpium extract.

Citri Reticulatae Pericarpium (CRP) is used as common health-care food and traditional Chinese medicine (TCM), which exerts pharmacological effects, such as anti-cardiovascular, anti-tumor, anti-oxidant, anti-inflammatory, anti-virus, hepatoprotective, blood pressure-lowering and neuroprotective. In this study, reliable, and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) methods were developed and validated for the determination of eleven active components in rat plasma after oral administration of the CRP extract. The results of this method exhibited that the specificity, linearity (r > 0.999), precision and accuracy (the coefficient of variation (CV) < 11.5 %), recovery (52.9-107.9 %), matrix effects (63.8-107.5 %), and stability (CV < 10.8 %) met all requirements for the quantitation of plasma samples. The pharmacokinetic results showed that the Tmax of flavone glycosides was less than 0.7 h, and that of polymethoxyflavones and volatile components were within 1-7 h. Meanwhile, the area-under-the-curve (AUC) and concentration maximum (Cmax) of hesperidin, nobiletin, tangeretin, and D-limonene were higher than those of the other components, suggesting that the plasma exposure levels of these constituents were higher in CRP. The present research lays a foundation for elucidating the therapeutic material basis and provides a reference for further scientific research and clinical application of CRP.

A Mitochondria-Targeted Photosensitizer for Combined Pyroptosis and Apoptosis with NIR-II Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

Overcoming tumor apoptosis resistance is a major challenge in enhancing cancer therapy. Pyroptosis, a lytic form of programmed cell death (PCD) involving inflammasomes, Gasdermin family proteins, and cysteine proteases, offers potential in cancer treatment. While photodynamic therapy (PDT) can induce pyroptosis by generating reactive oxygen species (ROS) through the activation of photosensitizers (PSs), many PSs lack specific subcellular targets and are limited to the first near-infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep-penetrating, organelle-targeted pyroptosis-mediated phototherapy is essential for cancer treatment strategies. Here, we synthesized four molecules with varying benzene ring numbers in thiopyrylium structures to preliminarily explore their photodynamic properties. The near-infrared-II (NIR-II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria-targeting abilities, and a large Stokes shift. Through nano-precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type-I ROS) upon 808 nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor-targeting ability via NIR-II fluorescence imaging (NIR-II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs-mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.

Psychological Status and Warfarin Therapy in Patients after Valve Replacement during the COVID-19 Pandemic: A Cross-sectional Study.

OBJECTIVE: The standardization of warfarin anticoagulant therapy is the key to lifelong treatment for patients after heart valve replacement. The present study explored the possible risk factors for anxiety and depression during the coronavirus disease 2019 (COVID-19) pandemic and analyzed the influence of psychological state on medication safety. METHODS: Eligible patients received a web-based questionnaire survey via the Wenjuanxing platform during outpatient visits. Depression was evaluated by the Self-Rating Depression Scale (SDS). Anxiety was evaluated by the Self-Rating Anxiety Scale (SAS). Medication adherence was evaluated by the Morisky scale. RESULTS: A total of 309 patients (aged 52.2±11.4 years) were included in the present study. The SDS score of all included patients was 36.9±9.4 points, of which 11 (3.6%) patients were diagnosed as having depression. The SAS score of all included patients was 43.1±9.3 points, of which 71 (23%) patients were diagnosed as having anxiety. Seven patients (2.3%) had both anxiety and depression. Logistic regression analysis revealed that only monthly income was an independent influencing factor for depression. Regarding anxiety, patients who underwent repeated operations had a 2.264-fold greater risk, and patients who received combination medication had a 2.140-fold greater risk. More bleeding events and coagulation disorders could be observed in patients with anxiety, depression or both. When anxiety occurred, patients showed worse medication adherence. However, depression had no significant effect on medication adherence. CONCLUSION: During the COVID-19 pandemic, the detection rate of mental illnesses such as anxiety and depression was high, which seriously affected the medication safety of warfarin. Analysis of its influencing factors will provide a reference for further standardized regulation of warfarin anticoagulant therapy after valve replacement.

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy.

Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 µM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

Chain electrospray ionization mass spectrometry for ultra-low volume sample analysis.

In this work, chain electrospray ionization (chain-ESI) was developed to efficiently ionize trace samples for mass spectrometry analysis. The primary ion source was found to have the ability to induce secondary electrospray ionization with an extraordinarily low sample consumption rate in the picoliters per minute (pLs/min). This allows low volume sample to generate substantial tandem mass spectrum (MS2) data for metabolite annotations. Notably, chain-ESI can effectively prevent the electro-redox reaction in the process of electrospray, so as to reflect the native state of the analytes. Furthermore, from a single Broussonetia papyrifera (B. papyrifera) trichome and a single A549 cancer cell, 1426 and 617 metabolites were detected respectively. All of those observations demonstrated that chain-ESI offers the advantages of direct, rapid analysis with extreme-low volumes and high coverage, enabling the measurement of bio-information in low volume samples.

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation.

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.

Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment.

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

Alkyl-Doping Enables Significant Suppression of Conformational Relaxation and Intermolecular Nonradiative Decay for Improved Near-Infrared Fluorescence Imaging.

Despite various efforts to optimize the near-infrared (NIR) performance of perylene diimide (PDI) derivatives for bio-imaging, convenient and efficient strategies to amplify the fluorescence of PDI derivatives in biological environment and the intrinsic mechanism studies are still lacking. Herein, we propose an alkyl-doping strategy to amplify the fluorescence of PDI derivative-based nanoparticles for improved NIR fluorescence imaging. The developed PDI derivative, OPE-PDI, shows much brighter in n-Hexane (HE) compared with that in other organic media, and the excited state dynamics investigation experimentally elucidates the solvent effect-induced suppression of intermolecular energy transfer and intramolecular nonradiative decay as the underlying mechanism for the fluorescence improvement. Theoretical calculations reveal the lowest reorganization energies of OPE-PDI in HE among various solvents, indicating the effectively suppressed conformational relaxation to support the strongest radiative decay. Inspired by this, an alkyl atmosphere mimicking HE is constructed by incorporating the octadecane into OPE-PDI-based nanoparticles, permitting up to 3-fold fluorescence improvement compared with the counterpart nanoparticles. Owing to the merits of high brightness, anti-photobleaching, and low biotoxicity for the optimal nanoparticles, they have been employed for probing and long-term monitoring of tumor. This work highlights a facile strategy for the fluorescence enhancement of PDI derivative-based nanoparticles.