Naoxintong capsule for treating cardiovascular and cerebrovascular diseases: from bench to bedside.

Naoxintong Capsule (NXT), a renowned traditional Chinese medicine (TCM) formulation, has been broadly applied in China for more than 30 years. Over decades, accumulating evidences have proven satisfactory efficacy and safety of NXT in treating cardiovascular and cerebrovascular diseases (CCVD). Studies have been conducted unceasingly, while this growing latest knowledge of NXT has not yet been interpreted properly and summarized comprehensively. Hence, we systematically review the advancements in NXT research, from its chemical constituents, quality control, pharmacokinetics, to its profound pharmacological activities as well as its clinical applications in CCVD. Moreover, we further propose specific challenges for its future perspectives: 1) to precisely clarify bioactivities of single compound in complicated mixtures; 2) to evaluate the pharmacokinetic behaviors of NXT feature components in clinical studies, especially drug-drug interactions in CCVD patients; 3) to explore and validate its multi-target mechanisms by integrating multi-omics technologies; 4) to re-evaluate the safety and efficacy of NXT by carrying out large-scale, multicenter randomized controlled trials. In brief, this review aims to straighten out a paradigm for TCM modernization, which help to contribute NXT as a piece of Chinese Wisdom into the advanced intervention strategy for CCVD therapy.

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Acovenosigenin A ß-glucoside mediates JAK2-STAT3 signaling pathway by targeting GP130 in A549 and H460 cells based on integrative analysis of transcriptome and proteome and biological verification.

Acovenosigenin A ß-glucoside (AAG) is a cardiac glycoside derived from Streptocaulon juventas (Lour.) Merr, which exhibited the potential in treating lung cancer in our previous research. However, the action mechanism remains unclear. In this research, JAK2-STAT3 signaling pathway was predicted to be the critical regulation pathway based on the integrative analysis of transcriptome and proteome. Western blotting and qPCR assays were performed to identify that AAG can regulate JAK2-STAT3 signaling pathway and its downstream genes, such as c-Myc, Survivin, Cyclin B1, CDK1, Bcl-2. And this action of AAG depended on the suppression of STAT3 phosphorylation and its nuclear translocation through the experiments of Immunofluorescence, transient transfection and cryptotanshinone treatment. Additionally, AAG was discovered to mediate the JAK2-STAT3 pathway in IL-6-driven A549 and H460 cells, which in turn inhibited cell proliferation, promoted mitochondria-related apoptosis, and arrested the cell cycle progression. By molecular docking analysis, CETSA and SIP experiments, the protein of GP130 was identified as the specific target of AAG in A549 and H460 cells. Further studies suggested that AAG inhibited JAK2-STAT3 pathway and its downstream genes by targeting GP130 in nude mice xenograft model in vivo. This research presented that AAG exhibits the promising potential in the treatment of NSCLC.

Ultra-Rapid Electrocatalytic H2O2 Fabrication over Mono-Species and High-Density Polypyrrolic-N Sites.

Electrocatalytic hydrogen peroxide (H2O2) production via two-electron oxygen reduction reaction (2e--ORR) features energy-saving and eco-friendly characteristics, making it a promising alternative to the anthraquinone oxidation process. However, the common existence of numerous 2e--ORR-inactive sites/species on electrocatalysts tends to catalyze side reactions, especially under low potentials, which compromises energy efficiency and limits H2O2 yield. Addressing this, a high surface density of mono-species pyrrolic nitrogen configurations is formed over a polypyrrole@carbon nanotube composite. Thermodynamic and kinetic calculation and experimental investigation collaboratively confirm that these densely distributed and highly selective active sites effectively promote high-rate 2e--ORR electrocatalysis and inhibit side reactions over a wide potential range. Consequently, an ultra-high and stable H2O2 yield of up to 67.9/51.2 mol g-1 h-1 has been achieved on this material at a current density of 200/120 mA cm-1, corresponding Faradaic efficiency of 72.8/91.5%. A maximum H2O2 concentration of 13.47 g L-1 can be accumulated at a current density of 80 mA cm-1 with satisfactory stability. The strategy of surface active site densification thus provides a promising and universal avenue toward designing highly active and efficient electrocatalysts for 2e--ORR as well as a series of other similar electrochemical processes.

Efficient and scalable prediction of stochastic reaction-diffusion processes using graph neural networks.

The dynamics of locally interacting particles that are distributed in space give rise to a multitude of complex behaviours. However the simulation of reaction-diffusion processes which model such systems is highly computationally expensive, the cost increasing rapidly with the size of space. Here, we devise a graph neural network based approach that uses cheap Monte Carlo simulations of reaction-diffusion processes in a small space to cast predictions of the dynamics of the same processes in a much larger and complex space, including spaces modelled by networks with heterogeneous topology. By applying the method to two biological examples, we show that it leads to accurate results in a small fraction of the computation time of standard stochastic simulation methods. The scalability and accuracy of the method suggest it is a promising approach for studying reaction-diffusion processes in complex spatial domains such as those modelling biochemical reactions, population evolution and epidemic spreading.

The protective effect of ginsenoside Rg1 against sepsis-induced lung injury through PI3K-Akt pathway: insights from molecular dynamics simulation and experimental validation.

Sepsis-induced acute lung injury (SALI) poses a significant threat with high incidence and mortality rates. Ginsenoside Rg1 (GRg1), derived from Ginseng in traditional Chinese medicine, has been found to reduce inflammation and protect lung epithelial cells against tissue damage. However, the specific roles and mechanisms by which GRg1 mitigates SALI have yet to be fully elucidated. In this context, we employed a relevant SALI mouse model, alongside network pharmacology, molecular docking, and molecular dynamics simulation to pinpoint GRg1's action targets, complemented by in vitro assays to explore the underlying mechanisms. Our research shows that GRg1 alleviates CLP-induced SALI, decreasing lung tissue damage and levels of serum proinflammatory factor IL-6, TNF-α, and IL-1ß, also enhancing the survival rate of CLP mice. A total of 116 common targets between GRg1 and ALI, with specific core targets including AKT1, VEGFA, SRC, IGF1, ESR1, STAT3, and ALB. Further in vitro experiments assessed GRg1's intervention effects on MLE-12 cells exposed to LPS, with qRT-PCR analysis and molecular dynamics simulations confirming AKT1 as the key target with the favorable binding activity for GRg1. Western blot results indicated that GRg1 increased the Bcl-2/Bax protein expression ratio to reduce apoptosis and decreased the high expression of cleaved caspase-3 in LPS-induced MLE-12 cells. More results showed significant increases in the phosphorylation of PI3K and AKT1. Flow cytometric analysis using PI and Annexin-V assays further verified that GRg1 decreased the apoptosis rate in LPS-stimulated MLE-12 cells (from 14.85 to 6.54%, p < 0.05). The employment of the AKT1 inhibitor LY294002 confirmed these trends, indicating that AKT1's inhibition negates GRg1's protective effects on LPS-stimulated MLE-12 cells. In conclusion, our research highlights GRg1's potential as an effective adjunct therapy for SALI, primarily by inhibiting apoptosis in alveolar epithelial cells and reducing pro-inflammatory cytokine secretion, thus significantly enhancing the survival rates of CLP mice. These beneficial effects are mediated through targeting AKT1 and activating the PI3K-AKT pathway.

Machine learning analysis of lab tests to predict bariatric readmissions.

The purpose of this study was to develop a machine learning model for predicting 30-day readmission after bariatric surgery based on laboratory tests. Data were collected from patients who underwent bariatric surgery between 2018 and 2023. Laboratory test indicators from the preoperative stage, one day postoperatively, and three days postoperatively were analyzed. Least absolute shrinkage and selection operator regression was used to select the most relevant features. Models constructed included support vector machine (SVM), generalized linear model, multi-layer perceptron, random forest, and extreme gradient boosting. Model performance was evaluated and compared using the area under the receiver operating characteristic curve (AUROC). A total of 1262 patients were included, of which 7.69% of cases were readmitted. The SVM model achieved the highest AUROC (0.784; 95% CI 0.696-0.872), outperforming other models. This suggests that machine learning models based on laboratory test data can effectively identify patients at high risk of readmission after bariatric surgery.

Evaluation of preoperative magnetic resonance imaging features and diagnostic effectiveness of grades II and III intracranial solitary fibroma.

OBJECTIVES: To explore the value of preoperative magnetic resonance imaging (MRI) characterization of intracranial solitary fibrous tumors (ISFT) and to evaluate the effectiveness of preoperative MRI features in predicting pathological grading. MATERIALS AND METHODS: This retrospective analysis comprised the clinical and preoperative MRI characterization of 55 patients with ISFT in our hospital, including 27 grade II cases and 28 grade III cases confirmed by postoperative pathology. Variables included age, sex, tumor location, cross-midline status, signal characteristics of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery (T2-FLAIR), and diffusion­weighted imaging (DWI), peritumoral edema, intralesional hemorrhage, focal necrosis/cystic degeneration, tumor empty vessel, maximum tumor diameter, maximum, minimum, and average values of apparent diffusion coefficient (ADCmax, ADCmin, and ADCmean), tumors enhancement mode, meningeal tail sign, skull invasion, cerebral parenchymal invasion, and venous sinus involvement. The independent samples t test or Mann-Whitney U test was performed to compare continuous data between the two groups, and the Pearson chi-squared test or Fisher's exact test was used to compare categorical data. In addition, bivariate logistic regression was performed to construct a comprehensive model, and receiver operating characteristic (ROC) curves were generated to calculate the areas under the curve (AUCs), thereby determining the value of each parameter in the differential diagnosis of grades II and III ISFT. RESULTS: The mean age at onset was similar between patients with grades II and III ISFT (46.77 ± 14.66 years and 45.82 ± 12.07 years, respectively). The proportions of men among patients with grades II and III ISFT were slightly higher than those of female patients (male/female: 1.25 [15/12] and 1.33 [16/12], respectively). There were significant differences between grades II and III ISFT in the T2-FLAIR and DWI signal characteristics, maximum, minimum, and average values of the apparent diffusion coefficient (ADCmax, ADCmin, and ADCmean), tumor location, and skull invasion (P = 0.001, P = 0.018, P = 0.000, P = 0.000, P = 0.000, P = 0.010, and P = 0.032, respectively). However, no significant differences were noted between grades II and III ISFT in age, sex, cross-midline status, T1WI and T2WI signal characteristics, peritumoral edema, intralesional hemorrhage, focal necrosis/cystic degeneration, tumor empty vessel shadow, enhancement mode, meningeal tail sign, maximum tumor diameter, brain parenchyma invasion, or venous sinus involvement (all P > 0.05). Moreover, binary logistic regression analysis showed that the model accuracy was 89.1% when ADCmin was included in the regression equation. Moreover, ROC curve analysis showed that the AUC of ADCmin was 0.805 (0.688, 0.922), sensitivity was 74.1%, specificity was 75.0%, and the cutoff value was 672 mm2/s. CONCLUSIONS: Grade III ISFT patients displayed more mixed T2-FLAIR signal characteristics and DWI signal characteristics than grade II patients, as shown by higher skull invasion and tumor mass collapse midline distribution and lower ADCmax, ADCmean, and ADCmin values. The ADCmin value was significant in the preoperative assignment of grades II and III ISFT, thereby contributing to enhanced accuracy in the imaging grading diagnosis of the disease.

Role of Th2, Th17 and Treg Cells and relevant cytokines in pathogenesis of allergic rhinitis.

OBJECTIVE: To explore the role of different cells and molecules in the pathogenesis of allergic rhinitis (AR) with positive Artemisia allergen by detecting their expression levels. METHODS: From January 2021 to December 2022,200 AR patients diagnosed in the Otolaryngology Clinic of Ordos Central Hospital were selected as the AR group, and 50 healthy people who underwent physical examination in the hospital during the same period were randomly selected as the healthy control (HC) group. The levels of GATA-3mRNA, RORγtmRNA and FoxP3mRNA in peripheral blood mononuclear cells were detected by real-time fluorescence quantitative PCR (qRT-PCR). The proportions of Th2, Th17 and Treg cells were detected by flow cytometry. The concentrations of IL-4, IL-5, IL-17 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The differences of transcription gene level, immune cell ratio and cytokine concentration between the two groups were analyzed. RESULTS: There was no difference in age and gender between the two groups. The levels of GATA-3mRNA and RORγtmRNA transcription genes in peripheral blood mononuclear cells, the percentage of Th2, Th17 and Treg immune cells, the levels of eosinophils and basophils in peripheral blood, the concentrations of IL-4, IL-5, IL-17, IL-10 cytokines and IgE in serum of AR patients were significantly higher than those in HC group (P < 0.05). IL-4 and IL-17 were positively correlated with total IgE level. CONCLUSION: The secretion of immune cells and cytokines in peripheral blood of AR patients is abnormal. Th2, Th17, Treg specific transcription factors and related cells and cytokines are involved in the occurrence and development of allergic rhinitis.

Preliminary investigation of nitric oxide release from upconverted nanoparticles excited at 808 nm near-infrared for brain tumors.

Upconverted UCNPs@mSiO2-NH2 nanoparticles were synthesized via thermal decomposition while employing the energy resonance transfer principle and the excellent near-infrared (NIR) light conversion property of up-conversion. The 808 nm NIR-excited photocontrolled nitric oxide (NO) release platform was successfully developed by electrostatically loading photosensitive NO donor Roussin's black salt (RBS) onto UCNPs@mSiO2-NH2, enabling the temporal, spatial, and dosimetric regulation of NO release for biological applications of NO. The release of NO ranged from 0.015⁓0.099 mM under the conditions of 2.0 W NIR excitation power, 20 min of irradiation time, and UCNPs@mSiO2-NH2&RBS concentration of 0.25⁓1.25 mg/mL. Therefore, this NO release platform has an anti-tumor effect. In vitro experiments showed that under the NIR light, at concentrations of 0.3 mg/mL and 0.8 mg/mL of UCNPs@mSiO2-NH2&RBS, the activity of glioma (U87) and chordoma (U-CH1) cells, as measured by CCK8 assay, was reduced to 50 %. Cell flow cytometry and Western Blot experiments showed that NO released from UCNPs@mSiO2-NH2&RBS under NIR light induced apoptosis in brain tumor cells. In vivo experiments employing glioma and chordoma xenograft mouse models revealed significant inhibition of tumor growth in the NIR and UCNPs@mSiO2-NH2&RBS group, with no observed significant side effects in the mice. Therefore, NO released by UCNPs@mSiO2-NH2&RBS under NIR irradiation can be used as a highly effective and safe strategy for brain tumor therapy.

Do Chinese HIV-infected Adult Patients with altered renal function need to adjust Tenofovir Disoproxil Fumarate Dosage? A Population Pharmacokinetics analysis.

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir(TFV), is an effective drug in treating patients infected with human immunodeficiency virus(HIV). Previous population pharmacokinetics(PPK) studies have showed the large variabilities in PK of TFV. Furthermore, limited information was known in Chinese populations. Therefore, the aim of this study was to characterize PPK of TDF in Chinese and identify factors that may affect its PK. TFV concentrations (n = 552) from 30 healthy subjects and 162 HIV-infected Chinese adult patients were pooled for PPK analysis by a nonlinear mixed-effects method. The PK of TFV was adequately described as a two-compartment model with first order absorption and elimination. The typical apparent clearance(CL/F) of TFV in 70-kg adults was 137 L/h, higher than that reported in Caucasians and Blacks(45.8-93L/h). Estimated glomerular filtration rate was identified to be a significant factor influencing CL/F. Monte Carlo simulation showed that the exposure of standard dosing regimen of TDF 300mg every 24 hours in Chinese people with mild renal impairment(60 to 90 ml/min/1.73m2) was close to that in individuals with normal renal function(90 mL/min). Dose adjustment is not required for patients with mild renal impairment. Our study might offer new clues for optimal dosing strategies in Chinese patients with HIV-infected.

Comparison of vonoprazan bismuth-containing triple therapy with quadruple therapy in Helicobacter pylori-infected treatment-naive patients: a prospective multicenter randomized controlled trial.

BACKGROUND AND AIM: Helicobacter pylori infection is linked to various gastrointestinal conditions, such as chronic active gastritis, peptic ulcers, and gastric cancer. Traditional treatment options encounter difficulties due to antibiotic resistance and adverse effects. Therefore, the aim of this study was to explore the effectiveness of a new treatment plan that combines vonoprazan (VPZ), amoxicillin, and bismuth for the eradication of H. pylori. METHODS: A total of 600 patients infected with H. pylori were recruited for this multicenter randomized controlled trial. Patients treated for H. pylori elimination were randomly assigned at a 1:1 ratio to receive 14 days of vonoprazan-based triple therapy (vonoprazan + amoxicillin + bismuth, group A) or standard quadruple therapy (esomeprazole + clarithromycin + amoxicillin + bismuth, group B). Compliance and adverse effects were tracked through daily medication and side effect records. All patients underwent a 13C/14C-urea breath test 4 weeks after treatment completion. RESULTS: Intention-to-treat (ITT) and per-protocol (PP) analyses revealed no substantial differences in H. pylori eradication rates between groups A and B (ITT: 83.7% vs 83.2%; PP: 90.9% vs 89.7%). However, significant differences were observed in the assessment of side effects (13.7% vs 28.6%, P < 0.001). Specifically, group A had significantly fewer "bitter mouths" than group B did (3.7% vs 16.2%, P < 0.001). CONCLUSION: Triple therapy comprising vonoprazan (20 mg), amoxicillin (750 mg), and bismuth potassium citrate (220 mg) achieved a PP eradication rate ≥90%, paralleling standard quadruple therapy, and had fewer adverse events and lower costs (¥306.8 vs ¥645.8) for treatment-naive patients.

Preoperative in-hospital delay increases postoperative morbidity and mortality in patients with acute appendicitis: A meta-analysis.

BACKGROUND: Complicated appendicitis is associated with high morbidity, mortality, and healthcare costs. However, the relationship of preoperative in-hospital delay >24 hours with complicated appendicitis and postoperative morbidity remains unclear. This meta-analysis investigated the effects of preoperative in-hospital delay on complicated appendicitis and postoperative morbidity in patients with acute appendicitis. MATERIALS AND METHODS: This study adheres to the PRISMA 2020 and AMSTAR 2 guidelines. The PubMed, Embase, Cochrane Library, and Web of Science databases up to October 14, 2023 (updated on March 16, 2024) were searched for randomized controlled trials (RCTs) and observational studies that evaluated the effect of preoperative in-hospital delays of >24 hours on acute appendicitis. Odds ratios (OR) and 95% confidence intervals were also determined. RESULTS: We yielded 18,130 records, of which 28 studies (512,881 patients) were included in the meta-analysis. The risk of bias was considered serious, moderate, and low for 24, 3, and 1 study, respectively. Although preoperative in-hospital delays of >24 hours were not associated with a higher risk of surgical site infection (OR 1.04, 95% CI 0.97, 1.12, P=0.25), in-hospital delays of >24 hours was a risk factor for complicated appendicitis (OR 1.60, 95% CI 1.25, 2.05, P=0.0002), and postoperative complications (OR 1.51, 95% CI 1.30, 1.75, P<0.00001). In addition, an in-hospital delay of >24 hours before surgery increased the OR of postoperative mortality (OR 1.81, 95% CI 1.33, 2.45, P=0.0001). The sensitivity analyses also confirmed the robustness of our results. CONCLUSIONS: An in-hospital delay of >24 hours is a risk factor for complicated appendicitis, postoperative complications, and mortality. Given the subsequent adverse outcomes of in-hospital delays, appendectomy should not be delayed for >24 hours.

Predicting the 28-day prognosis of acute-on-chronic liver failure patients based on machine learning.

BACKGROUND: We aimed to establish a prognostic predictive model based on machine learning (ML) methods to predict the 28-day mortality of acute-on-chronic liver failure (ACLF) patients, and to evaluate treatment effectiveness. METHODS: ACLF patients from six tertiary hospitals were included for analysis. Features for ML models' development were selected by LASSO regression. Models' performance was evaluated by area under the curve (AUC) and accuracy. Shapley additive explanation was used to explain the ML model. RESULTS: Of the 736 included patients, 587 were assigned to a training set and 149 to an external validation set. Features selected included age, hepatic encephalopathy, total bilirubin, PTA, and creatinine. The eXtreme Gradient Boosting (XGB) model outperformed other ML models in the prognostic prediction of ACLF patients, with the highest AUC and accuracy. Delong's test demonstrated that the XGB model outperformed Child-Pugh score, MELD score, CLIF-SOFA, CLIF-C OF, and CLIF-C ACLF. Sequential assessments at baseline, day 3, day 7, and day 14 improved the predictive performance of the XGB-ML model and can help clinicians evaluate the effectiveness of medical treatment. CONCLUSIONS: We established an XGB-ML model to predict the 28-day mortality of ACLF patients as well as to evaluate the treatment effectiveness.

Investigating the mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease using network pharmacology and molecular docking.

Go deeply into the molecular mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease (DKD) by network pharmacology and molecular docking. Fuling-Banxia-Dafupi is a pair of traditional Chinese medicine for diabetic kidney disease, which can slow down the development of diabetic kidney disease. Screening active components and targets of Fuling-Banxia-Dafupi using the TCMSP database. The Uniprot database was also used to identify effective drug targets. DKD-related Targets were retrieved from the Gene Cards database, and the overlap between these targets and Fuling-Banxia-Dafupi was obtained. GO and KEGG pathway concentration analyses were showed using Metascape, and the results were presented by the microcredit platform. A total of 616 active ingredients and targets were confrimed and intersected with 3,951 diabetic neuropathy-related targets, resulting in 306 common targets. Baicalein and cerevisterol are the core components of Fuling-Banxia-Dafupi, and the key targets are TP53, SRC, and STAT 3. PI3K-Akt signalling pathway is an important pathway. The molecular docking indicated that its main active components and target proteins have good binding activity.

Fragment-based approach to study fungicide-biomimetic membrane interactions.

In this study, the molecular interactions of the allylamine-type fungicide butenafine and a set of substructures ("fragments") with liposomes mimicking biological membranes were studied to gain a better understanding of the structural factors governing membrane affinity and perturbation. Specifically, drug/fragment-membrane interactions were investigated using an interdisciplinary approach involving micro differential scanning calorimetry, open-tubular capillary electrochromatography, nanoplasmonic sensing, and quartz crystal microbalance. By incubating the drug and the fragment compounds with liposomes with varying lipid composition or by externally adding the compounds to preformed liposomes, a detailed mechanistic picture on the underlying drug/fragment-membrane interactions was obtained. The nature and the degree of ionisation of polar head groups of the lipids had a major influence on the nature of drug-membrane interactions, and so had the presence and relative concentration of cholesterol within the membranes. The in-depth understanding of drug/fragment-membranes interactions established by the presented interdisciplinary fragment-based approach may be useful in guiding the design and early-stage evaluation of prospective antifungal drug candidates, and the discovery of agents with improved membrane penetrating characteristics in general.

A Generalized Coordination Engineering Strategy for Single-Atom Catalysts toward Efficient Hydrogen Peroxide Electrosynthesis.

Designing non-noble metal single-atom catalysts (M-SACs) for two-electron oxygen reduction reaction (2e-ORR) is attractive for the hydrogen peroxide (H2O2) electrosynthesis, in which the coordination configuration of the M-SACs essentially affects the reaction activity and product selectivity. Though extensively investigated, a generalized coordination engineering strategy has not yet been proposed, which fundamentally hinders the rational design of M-SACs with optimized catalytic capabilities. Herein, a generalized coordination engineering strategy is proposed for M-SACs toward H2O2 electrosynthesis via introducing heteroatoms (e.g., oxygen or sulfur atoms) with higher or lower electronegativity than nitrogen atoms into the first sphere of metal-N4 system to tailor their electronic structure and adjust the adsorption strength for *OOH intermediates, respectively, thus optimizing their electrocatalytic capability for 2e-ORR. Specifically, the (O, N)-coordinated Co SAC (Co-N3O) and (S, N)-coordinated Ni SAC (Ni-N3S) are precisely synthesized, and both present superior 2e-ORR activity (Eonset: ≈0.80 V versus RHE) and selectivity (≈90%) in alkaline conditions compared with conventional Co-N4 and Ni-N4 sites. The high H2O2 yield rates of 14.2 and 17.5 moL g-1 h-1 and long-term stability over 12 h are respectively achieved for Co-N3O and Ni-N3S. Such favorable 2e-ORR pathway of the catalysts is also theoretically confirmed by the kinetics simulations.

Duplex Real-Time Fluorescent Quantitative PCR Assays for the Detection of Toxigenic Microcystis Genotypes Based on SNP/InDel Variation in mcy Gene Cluster.

In this study, the toxigenic characteristics of 14 strains of Microcystis were analyzed, and single nucleotide polymorphism (SNP) and insertion/deletion (InDel) loci in microcystin synthetase (mcy) gene clusters were screened. Based on SNP and InDel loci associated with the toxigenic characteristics, primers and TaqMan or Cycling fluorescent probes were designed to develop duplex real-time fluorescent quantitative PCR (FQ-PCR) assays. After evaluating specificity and sensitivity, these assays were applied to detect the toxigenic Microcystis genotypes in a shrimp pond where Microcystis blooms occurred. The results showed a total of 2155 SNP loci and 66 InDel loci were obtained, of which 12 SNP loci and 5 InDel loci were associated with the toxigenic characteristics. Three duplex real-time FQ-PCR assays were developed, each of which could quantify two genotypes of toxigenic Microcystis. These FQ-PCR assays were highly specific, and two Cycling assays were more sensitive than TaqMan assay. In the shrimp pond, six genotypes of toxigenic Microcystis were detected using the developed FQ-PCR assays, indicating that above genotyping assays have the potential for quantitative analysis of the toxigenic Microcystis genotypes in natural water.

Extracellular vesicle surface display of αPD-L1 and αCD3 antibodies via engineered late domain-based scaffold to activate T-cell anti-tumor immunity.

Extracellular vesicles (EVs) are emerging as promising carriers for the delivery of therapeutic biologics. Genetic engineering represents a robust strategy for loading proteins of interest into EVs. Identification of EV-enriched proteins facilitates protein cargo loading efficiency. Many EV-enriched proteins are sorted into EVs via an endosomal sorting complex required for transport (ESCRT)-dependent pathway. In parallel, viruses hijack this EV biosynthesis machinery via conserved late domain motifs to promote egress from host cells. Inspired by the similarity of biogenesis between EVs and viruses, we developed a synthetic, Late domain-based EV scaffold protein that enables the display of a set of single chain variable fragments (scFvs) on the EV surface. We named this scaffold the Late domain-based exosomal antibody surface display platform (LEAP). We applied the LEAP scaffold to reprogramme HEK293T cell-derived EVs to elicit T-cell anti-tumor immunity by simultaneously displaying αPD-L1 and αCD3 scFvs on the EV surface (denoted as αPD-L1×αCD3 bispecific T-cell engaging exosomes, BiTExos). We demonstrated that αPD-L1×αCD3 BiTExos actively redirected T cells to bind to PD-L1+ tumor cells, promoting T-cell activation, proliferation and tumoricidal cytokine production. Furthermore, the αPD-L1×αCD3 BiTExos promoted T-cell infiltration into the tumor microenvironment to mitigate the tumor burden in vivo. Our study suggested that the LEAP scaffold may serve as a platform for EV surface display and could be applied for a broad range of EV-based biomedical applications.

Magnetic relaxation switching immunosensor based on polystyrene microcolumn and tyramine signal amplification for ultrasensitive and user-friendly detection of aflatoxin B1 in corn.

Aflatoxin B1 is highly mutagenic in humans, and long-term exposure can impair immunity and increase the risk of cancer. It is imperative to develop immunoassays with convenient operation and high sensitivity to detect aflatoxin B1. This study presents a polystyrene microcolumn-mediated magnetic relaxation switching immunosensor based on a tyramine signal amplification strategy for detecting aflatoxin B1. An environmentally friendly hand-held polystyrene microcolumn was designed as an effective immunoreaction carrier, remaining 91% efficiency after 12 repeated uses. And the microcolumn provides a user-friendly procedure for rapid separation and reagent switching within 3 s by simple stirring in solution. The combination of a strong anti-interference magnetic relaxation switching biosensing and an efficient tyramine signal amplification enables the quantitative detection of aflatoxin B1 in the range of 0.01-10 ng/mL, with a limit of detection of 0.006 ng/mL. This method has potential application in the rapid detection of trace food contaminants.