MRI-based radiomics signatures for preoperative prediction of Ki-67 index in primary central nervous system lymphoma.

PURPOSE: The aim of this study was to develop and validate radiomics signatures based on MRI for preoperative prediction of Ki-67 proliferative index (PI) expression in primary central nervous system lymphoma (PCNSL). METHODS: A total of 341 patients with PCNSL were retrospectively analyzed, including 286 patients in one center as the training set and 55 patients in another two centers as the external validation set. Radiomics features were extracted and selected from preoperative contrast-enhanced T1-weighted images, fluid attenuation inversion recovery to build radiomics signatures according to the Ki-67 PI. The predictive performances of the radiomics model were evaluated using four classifiers including random forest, K-Nearest Neighbors, Neural Network and Decision Tree. A combined model was built by incorporating radiomics signature, clinical variables and MRI radiological characteristics using multivariate logistic regression analysis, and a nomogram was established to predict the expression of Ki-67 individually. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: Radiomics signatures were independent predictors of the expression level of Ki-67 (OR: 2.523, P < 0.001). RF radiomics models had the highest accuracy (0.934 in the training set and 0.811 in the external validation set) and F1 Score (0.920 in the training set and 0.836 in the external validation set). The clinic-radiologic-radiomics nomogram showed better predictive performance with AUCs of 0.877(95 % CI: 0.837-0.918) in the training set and 0.866(95 % CI: 0.774-0.957) in the external validation set. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram. CONCLUSIONS: Nomograms integrating MRI-based radiomics and clinical-radiological characteristics could effectively predict Ki-67 PI in primary PCNSL.

Establishment of the Diagnostic Signature of Ferroptosis Genes in Multiple Sclerosis.

Ferroptosis is a novel form of membrane-dependent cell death that differs from other cell death modalities such as necrosis, apoptosis, and autophagy. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system primarily affecting brain and spinal cord neurons. Although the pathogenesis of these two conditions may seem unrelated, recent studies have indicated a connection between ferroptosis and multiple sclerosis. In fact, ferroptosis plays a significant role in the development of MS, as evidenced by the presence of elevated iron levels and iron metabolism abnormalities in the brains, spinal cords, and other neurons of MS patients. These abnormalities disrupt iron homeostasis within cells, leading to the occurrence of ferroptosis. However, there is currently a lack of research on the diagnostic value of ferroptosis-related genes in multiple sclerosis. In this study, we employed bioinformatics methods to identify ferroptosis-related genes (ATM, GSK3B, HMGCR, KLF2, MAPK1, NFE2L1, NRAS, PCBP1, PIK3CA, RPL8, VDAC3) associated with the diagnosis of multiple sclerosis and constructed a diagnostic model. The results demonstrated that the diagnostic model accurately identified the patients' condition. Subsequently, subgroup analysis was performed based on the expression levels of ferroptosis-related genes, dividing patients into high and low expression groups. The results showed differences in immune function and immune cell infiltration between the two groups. Our study not only confirms the correlation between ferroptosis and multiple sclerosis but also demonstrates the diagnostic value of ferroptosis-related genes in the disease. This provides guidance for clinical practice and direction for further mechanistic research.

Predictive Value of Corrected 18 F-FDG PET/CT Baseline Parameters for Primary DLBCL Prognosis: A Single-center Study.

Objective The purpose of this study was to evaluate the prognostic significance of corrected baseline metabolic parameters in fluorodeoxyglucose positron emission tomography imaging ( 18 F-FDG PET/CT) for 3-year progression-free survival (PFS) in patients with primary diffuse large B cell lymphoma (DLBCL). Patients and Methods Retrospective clinical and pathological data were collected for 199 patients of DLBCL diagnosed between January 2018 and January 2021. All patients underwent 18 F-FDG PET/CT scans without any form of treatment. The corrected maximum standardized uptake value (corSUVmax), corrected mean standardized uptake value (corSUVmean), corrected whole-body tumor metabolic volume sum (corMTVsum), and corrected total lesion glycolysis of whole body (corTLGtotal) were corrected using the SUVmean in a 1-cm diameter mediastinal blood pool (MBP) from the descending thoracic aorta of patients. Kaplan-Meier survival curves and Cox regression were used to examine the predictive significance of corrected baseline metabolic parameters on 3-year PFS of patients. The incremental values of corrected baseline metabolic parameters were evaluated by using Harrell's C-indices, receiver operating characteristic, and Decision Curve Analysis. Results The multivariate analysis revealed that only the National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) and corMTVsum had an effect on 3-year PFS of patients ( p < 0.05, respectively). The Kaplan-Meier survival analysis demonstrated significant differences in PFS between the risk groups classified by corSUVsum, corMTVsum, and corTLGtotal (log-rank test, p < 0.05). The predictive model composed of corMTVsum and corTLGtotal surpasses the predictive performance of the model incorporating MTVsum and TLGtotal. The optimal performance was observed when corMTVsum was combined with NCCN-IPI, resulting in a Harrell's C index of 0.785 and area under the curve values of 0.863, 0.891, and 0.947 for the 1-, 2-, and 3-year PFS rates, respectively. Conclusion The corMTVsum offers significant prognostic value for patients with DLBCL. Furthermore, the combination of corMTVsum with the NCCN-IPI can provide an accurate prediction of the prognosis.

Amphiphilic Dendronized Copolymer-Encapsulated Au, Ag and Pd Nanoparticles for Catalysis in the 4-Nitrophenol Reduction and Suzuki-Miyaura Reactions.

The branched structures of dendronized polymers can provide good steric stabilization for metal nanoparticle catalysts. In this work, an amphiphilic dendronized copolymer containing hydrophilic branched triethylene glycol moieties and hydrophobic branched ferrocenyl moieties is designed and prepared by one-pot ring-opening metathesis polymerization, and is used as the stabilizer for metal (Au, Ag and Pd) nanoparticles. These metal nanoparticles (Au nanoparticles: 3.5 ± 3.0 nm; Ag nanoparticles: 7.2 ± 4.0 nm; Pd nanoparticles: 2.5 ± 1.0 nm) are found to be highly active in both the 4-nitrophenol reduction and Suzuki-Miyaura reactions. In the 4-nitrophenol reduction, Pd nanoparticles have the highest catalytic ability (TOF: 2060 h-1). In addition, Pd nanoparticles are also an efficient catalyst for Suzuki-Miyaura reactions (TOF: 1980 h-1) and possess good applicability for diverse substrates. The amphiphilic dendronized copolymer will open a new door for the development of efficient metal nanoparticle catalysts.

An ionic liquid-modified PEDOT/Ti3C2TX based molecularly imprinted electrochemical sensor for pico-molar sensitive detection of L-Tryptophan in milk.

L-Tryptophan (L-Trp) is essential for the human body and can only be obtained externally. It is important to develop a method to efficiently detect L-Trp in food. In this work, ionic liquid (IL) modified poly(3,4-ethylendioxythiophene)/ Titanium carbide (PEDOT/Ti3C2TX) was used as a substrate material to improve detection sensitivity. Molecular imprinted polymers (MIP) film for specific recognition of L-Trp was fabricated on the surface of modified electrodes using electrochemical polymerization. The monitoring results showed that the molecularly imprinted electrochemical sensors (MIECS) exhibited good linearity ranges (10-6 - 0.1 µM and 0.1-100 µM) with a low detection limit (LOD) of 2.09 × 10-7 µM. In addition, the MIECS exhibited remarkable stability, reproducibility, and immunity to interference. A good recovery (93.54-99.59%) was demonstrated in the detection of milk. The sensor was expected to be developed as a highly selective and sensitive portable assay, and applied to the detection of L-Trp in food.

A magnesium screw with optimized geometry exhibits improved corrosion resistance and favors bone fracture healing.

Stress-induced corrosion impairs the mechanical integrity of magnesium (Mg) and its alloys as potential orthopedic implants. Although there has been extensive work reporting the effects of stress on Mg corrosion in vitro, the geometric design principles of the Mg-based orthopedic devices still remain largely unknown. In this work, a numerical simulation model mimicking fractured bone fixation and surgical animal models were applied to investigate the effects of the geometric design of Mg screws on the stress distribution and the stress-induced degradation behavior. Finite element (FE) analysis was used for calculation of stress concentrations around the Mg screws, with different thread type, thread pitch, and thread width. Afterward, the Mg screws of the pre-optimization and post-optimization groups exhibiting the highest and lowest stress concentrations, respectively, were implanted in the fractured distal femora and back subcutaneous tissue of rabbits. Encouragingly, there was a significant difference between the pre-optimization and the post-optimization groups in the degradation rate of the stressed screw parts located around the fracture line. Interestingly, there was no significant difference between the two groups in the degradation rate of the non-stressed screw parts. Consistently, the Mg screw post-optimization exhibited a significantly lower degradation rate than that pre-optimization in the back subcutaneous implantation model, which generated stress in the whole screw body. The alteration in geometric design did not affect the corrosion rate of the Mg screws in an immersion test without load applied. Importantly, an accelerated new bone formation with less fibrous encapsulation around the screws was observed in the Mg group post-optimization relative to the Mg group pre-optimization and the poly (lactic acid) group. Geometry optimization may be a promising strategy to reduce stress-induced corrosion in Mg-based orthopedic devices. STATEMENT OF SIGNIFICANCE: Stress concentrations influence corrosion characteristics of magnesium (Mg)-based implants. The geometric design parameters, including thread type, thread pitch, and thread width of the Mg screws, were optimized through finite element analysis to reduce stress concentrations in a fractured model. The Mg screws with triangular thread type, 2.25 mm pitch, and 0.3 mm thread width, exhibiting the lowest maximum von Mises stress, showed a significant decrease in the volume loss relative to the Mg screws pre-optimization. Compared with the Mg screw pre-optimization and the poly(lactic acid) screw, the Mg screw post-optimization favored new bone formation while inhibiting fibrous encapsulation. Collectively, optimization in the geometric design is a promising approach to reduce stress-induced corrosion in Mg-based implants.

Curcumin and silver nanoparticles loaded antibacterial multifunctional pectin/gelatin films for food packaging applications.

Renewable biomass-based materials have a huge potential to replace petroleum-based products in food packaging. Herein, pectin/gelatin films loaded with curcumin and silver nanoparticles (AgNPs) are prepared by solution-pouring technology to serve as antimicrobial multifunctional food packaging films. AgNPs and curcumin are found to equally distribute in the films. Fourier transform infrared spectroscopy (FT-IR) reveal the hydrogen bonding and electrostatic interaction among curcumin, AgNPs, pectin and gelatin. The composite films show good antioxidant activity, mechanical performance, hydrophobicity and antibacterial ability. The films of P-GCA 0.5 showed 99.57 ± 0.16 % and 100 % inhibition against E. coli and S. aureus, respectively. The films also demonstrate excellent water vapor barrier qualities. In addition, the composite films possess pH-responsive color change behaviors from yellow (pH 3-8) to light red (pH 8-9) to dark red (pH 11-12), which is suitable for monitoring the freshness of shrimp packaging based on pH changes during deterioration process. As sustainable biomass-based materials, the multifunctional composite films are promising in intelligent food packaging applications.

Identification of water pollution sources and analysis of pollution trigger conditions in Jiuqu River, Luxian County, China.

Against the backdrop of ecological conservation and high-quality development in the Yangtze River Basin, there is an increasing demand for enhanced water pollution prevention and control in small watersheds. To delve deeper into the intricate relationship between pollutants and environmental features, as well as explore the key factors triggering pollution and their corresponding warning thresholds, this study was conducted along the Jiuqu River, a strategically managed unit in the upstream region of the Yangtze River, between 2022 and 2023. A total of seven monitoring sites were established, from which 161 valid water samples were collected. The k-nearest neighbors mutual information (KNN-MI) technique indicated that water temperature (WT) and relative humidity (RH) were the main environmental factors. The principal component analysis (PCA) of ten water quality parameters and three environmental factors unveiled the distinguishing characteristics of the primary pollution sources. Consequently, the pollution sources were categorized as treated wastewater > groundwater runoff > phytoplankton growth > abstersion wastewater > agricultural drainage. Furthermore, the regression decision tree (RDT) algorithm was used to explore the combined effects between pollutants and environmental factors, and to provide visual decision-making process and quantitative results for understanding the triggering mechanism of organic pollution in Jiuqu River. It conclusively identifies total phosphorus (TP) as the predominant triggering parameter with the threshold of 0.138 mg/L. The study is helpful to deal with potential water pollution problems preventatively and shows the interpretability and predictive performance of the RDT algorithm in water pollution prevention.

Highly sensitive electrochemical sensing of norfloxacin by molecularly imprinted composite hollow spheres.

Poly (3,4-ethylenedioxythiophene) (PEDOT)-based molecularly imprinted electrochemical sensors have attracted widespread attention for monitoring contaminants in food and the environment. However, there are still problems such as poor hydrophilicity, easy agglomeration, and low selectivity in its preparation. In this work, a novel molecularly imprinted composite hollow sphere was prepared by a molecular imprinting technique using nitrogen-doped hollow carbon spheres as matrix material, and PEDOT and poly(methacrylic acid) as monomers. The selective binding capabilities and mechanism of the material to norfloxacin (NOR) were systematically investigated. Then the material-based sensor was constructed, and its electrochemical detection performance toward NOR was thoroughly studied. The sensor exhibited a wide linear range (0.0005-31 µM), a low detection limit (0.061 nM), satisfactory immunity to interference and stability. Besides, the sensor displayed better sensitivity and reliability (spiked recoveries of 98.0-105.2%, relative standard deviation of 3.45-5.69%) for detecting NOR in lake water, honey, and milk than high-performance liquid chromatography. This work provides a new strategy for developing poly(3,4-ethylenedioxythiophene)-based molecularly imprinted electrochemical sensors.

Sodium carboxymethyl cellulose and MXene reinforced multifunctional conductive hydrogels for multimodal sensors and flexible supercapacitors.

With the growing demand for eco-friendly materials in wearable smart electronic devices, renewable, biocompatible, and low-cost hydrogels based on natural polymers have attracted much attention. Cellulose, as one of the renewable and degradable natural polymers, shows great potential in wearable smart electronic devices. Multifunctional conductive cellulose-based hydrogels are designed for flexible electronic devices by adding sodium carboxymethyl cellulose and MXene into polyacrylic acid networks. The multifunctional hydrogels possess excellent mechanical property (stress: 310 kPa; strain: 1127 %), toughness (206.67 KJ m-3), conductivity (1.09 ± 0.12 S m-1) and adhesion (82.19 ± 3.65 kPa). The multifunctional conductive hydrogels serve as strain sensors (Gauge Factor (GF) = 5.79, 0-700 % strain; GF = 14.0, 700-900 % strain; GF = 40.36, 900-1000 % strain; response time: 300 ms; recovery time: 200 ms) and temperature sensors (Temperature coefficient of resistance (TCR) = 2.5755 °C-1 at 35 °C- 60 °C). The sensor detects human activities with clear and steady signals. A distributed array of flexible sensors is created to measure the magnitude and distribution of pressure and a hydrogel-based flexible touch keyboard is also fabricated to recognize writing trajectories, pressures and speeds. Furthermore, a flexible hydrogel-based supercapacitor powers the LED and exhibits good cyclic stability over 15,000 charge-discharge cycles.

Maternal Administration of Acetaminophen Affects Meiosis Through its Metabolite NAPQI Targeting SIRT7 in Fetal Oocytes.

Aim: Acetaminophen (APAP) is clinically recommended as analgesic and antipyretic among pregnant women. However, accumulating laboratory evidence shows that the use of APAP during pregnancy may alter fetal development. Since fetal stage is a susceptible window for early oogenesis, we aim to assess the potential effects of maternal administration of APAP on fetal oocytes. Results: Pregnant mice at 14.5 dpc (days post-coitus) were orally administered with APAP (50 and 150mg/kg.bw/day) for 3 days; meanwhile, 14.5 dpc ovaries were collected and cultured with APAP or its metabolite N-acetyl-p-benzoquinone imine (NAPQI; 5 and 15 µM) for 3 days. It showed that APAP caused meiotic aberrations in fetal oocytes through its metabolite NAPQI, including meiotic prophase I (MPI) progression delay and homologous recombination defects. Co-treatment with nicotinamide (NAM) or nicotinamide riboside chloride (NRC), nicotinamide adenine dinucleotide (NAD+) supplements, efficiently restored the MPI arrest, whereas the addition of the inhibitor of sirtuin 7 (SIRT7) invalidated the effect of the NAD+ supplement. In addition, RNA sequencing revealed distorted transcriptomes of fetal ovaries treated with NAPQI. Furthermore, the fecundity of female offspring was affected, exhibiting delayed primordial folliculogenesis and puberty onset, reduced levels of ovarian hormones, and impaired developmental competence of MII oocytes. Innovation: These findings provide the first known demonstration that NAPQI, converted from maternal administration of APAP, disturbs meiotic process of fetal oocytes and further impairs female fecundity in adulthood. The concomitant oral dosing with NAM further supports the benefits of NAD+ supplements on oogenesis. Conclusion: Short-term administration of APAP to pregnant mouse caused meiotic aberrations in fetal oocytes by its metabolite NAPQI, whereas co-treatment with NAD+ supplement efficiently relieves the adverse effects by interacting with SIRT7.

ZnO-Ti3C2TX composites supported on polyacrylic acid/chitosan hydrogels as high-efficiency and recyclable photocatalysts for norfloxacin degradation.

Photocatalysts immobilized on hydrogels is a win-win mode, which not only improves photocatalysis but also successfully prevents catalyst loss, making it easy to separate and reuse during catalytic process. Here, ZnO-Ti3C2TX photocatalysts are loaded into the chitosan/polyacrylic acid hydrogel networks, realizing the efficiently photocatalytic degradation of norfloxacin. The chitosan-based composite hydrogel features rich functional groups and a dense pore structure, which is beneficial to antibiotic enrichment and photocatalytic degradation. The effects of different catalyst ratios, dosage, initial concentrations and pH on the degradation efficiency are investigated. The norfloxacin degradation rate constant is 0.012 min-1 and its degradation efficiency reaches up to 90 % after 240 min. Importantly, the photocatalytic composite hydrogel still retains 85 % degradation efficiency after 6 cycles. Moreover, e- plays a significant role in the degradation process. This work converts the traditional powder photocatalysts into bulk photocatalysts (photocatalytic hydrogels) to accomplish efficient degradation and rapid recycling for contaminant removal.

PEDOT-embellished Ti3C2Tx nanosheet supported Pt-Pd bimetallic nanoparticles as efficient and stable methanol oxidation electrocatalysts.

Exploiting high-efficiency and durable electrocatalysts toward the methanol oxidation reaction (MOR) is crucial for the advancement of direct methanol fuel cells (DMFCs). Herein, we demonstrate the loading of platinum-palladium bimetallic nanoparticles (Pt-Pd NPs) onto poly(3,4-ethylenedioxythiophene) (PEDOT)-embellished titanium carbide (Ti3C2Tx) nanosheets as the electrocatalyst (Ti3C2Tx/PEDOT/Pt-Pd) via a facile and rapid chemical reduction-assisted one-pot hydrothermal process. The structural and morphological analyses of Ti3C2Tx/PEDOT/Pt-Pd indicate that the three-dimensional (3D) hybrid structure formed between PEDOT and Ti3C2Tx provides a sizable active surface and more active sites, which enhances the homogeneous dispersion of the Pt-Pd NPs and facilitates mass transfer. The Schottky junctions formed between PEDOT and Pt-Pd NPs contribute to charge transfer. The electronic effects and synergistic interactions between the support and catalyst favor the electrocatalytic activity of the catalyst. The electrochemical test results reveal that the Ti3C2Tx/PEDOT/Pt-Pd catalyst has prominent electrocatalytic capability for the MOR. Compared with Ti3C2Tx/Pt-Pd and commercial Pt/C catalysts, the Ti3C2Tx/PEDOT/Pt-Pd catalyst has a larger electrochemical activity surface area (ECSA = 122 m2 g-1) and higher mass activity (MA = 1445.4 mA mg-1), as well as better CO tolerance and more reliable long-term durability (a peak current density retention of 71% after 5200 s).

Circulating lncRNAs NONHSAT054669.2 and ENST00000525337 can be used as early biomarkers of gestational diabetes mellitus.

Early diagnosis can help prevent and reduce the adverse effects of gestational diabetes mellitus (GDM). This study intended to investigate key circulating long non-coding RNAs (lncRNAs) as novel biomarkers for diagnosis of GDM at the early stages. First, lncRNA microarray analysis was conducted for plasma samples of GDM women before delivery and 48 h after delivery. The expression of differentially expressed lncRNAs in clinical samples at different trimesters was randomly validated by quantitative polymerase chain reaction (PCR). Moreover, the correlation between lncRNA expression and oral glucose tolerance test (OGTT) level in GDM women during the second trimester was analyzed, followed by evaluating the diagnostic value of key lncRNAs during different trimesters using receiver operating characteristic (ROC) curve. Higher NONHSAT054669.2 expression and lower ENST00000525337 expression were revealed in GDM women before delivery relative to 48 h after delivery (P < 0.05). The expression of NONHSAT054669.2 and ENST00000525337 in GDM women during the first and second trimesters was dramatically higher than pregnant women (P < 0.05) with normal glucose tolerance (NGT). During the second trimester, NONHSAT054669.2 expression was positively related to OGTT level at 1 h (r = 0.41455, P < 0.001). Furthermore, ROC curve analysis revealed that ENST00000525337 alone, NONHSAT054669.2 alone, and their combination had high diagnostic value for GDM during the first (area under the ROC curve (AUC) = 0.979, 0.956, and 0.984, respectively) and second (AUC = 0.829, 0.809, and 0.838, respectively) trimesters (all P < 0.001). The plasma level of NONHSAT054669.2 and ENST00000525337 may be applied as novel diagnostic biomarkers for early diagnosis of GDM.

Bimetallic (AuAg, AuPd and AgPd) nanoparticles supported on cellulose-based hydrogel for reusable catalysis.

Biopolymer-derived hydrogels with low-cost and sustainable features have been considered as fascinating supported materials for metal nanoparticles. Cellulose, as the most abundant biopolymer, is a renewable raw material to prepare biopolymer-derived hydrogels for catalysis. Here, a cellulose-based hydrogel is designed to load bimetallic (AuAg, AuPd and AgPd) nanoparticles. 4-Nitrophenol reduction and Suzuki-Miyaura coupling reactions are selected to evaluate and compare the catalytic performance of the resulting bimetallic nanoparticle-loaded cellulose-based composite hydrogels. The bimetallic nanocomposite hydrogels are easy to be recycled over 10 times during the catalytic experiments and possess good applicability and generality for various substrates. The catalytic activity of bimetallic nanocomposite hydrogels was compared with recent literatures. In addition, the possible catalytic mechanism is also proposed. This work is expected to give a new insight for designing and preparing bimetallic nanoparticle-based cellulose hydrogels and proves its applicability and prospect in the catalytic field.

Characteristics of ginsenoside Rd-induced effects on rat intestinal contractility with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a very common refractory disease. Its exact pathophysiological mechanism is still unclear. Despite the availability of plentiful drugs to control IBS, most patients do not respond well. Ginsenoside Rd is one of the major active components of Panax ginseng, which has been verified to produce various pharmacological actions. However, the role of ginsenoside Rd in modulating smooth muscle contractility is still undefined. The aim of this study is to investigate the effects of ginsenoside Rd on intestinal contractility and related mechanisms in IBS.

A WeChat-Based Rehabilitation Platform for Children and Adolescents with Congenital Heart Disease to Promote Cardiac FITness (HeartFIT): Protocol for a Mixed-Methods Strategy from Evidence-Based Design to Pilot Study.

Progress in medical and surgical care has tremendously improved the survival rates of children with congenital heart disease (CHD). However, reduced aerobic capacity and health-related issues remain a threaten to quality survival and prevention of related complications among children and adolescents with CHD. This research program aims to develop and evaluate a WeChat-based health platform (HeartFIT) to facilitate cardiac rehabilitation and promote physical fitness for this rapidly expanding young population. The study protocol describes the use of an iterative process of using a mixed-methods strategy to develop, refine, and pilot test the proposed HeartFIT platform. A sequential problem-solving process comprising four iterative phases with ongoing end-user input will be implemented. In phase 1, relevant literature was systematically reviewed (completed) and then child-parent dyads will be interviewed to understand the broad context and the requirements and considerations of the target population toward the WeChat-based rehabilitation platform. In phase 2, key features and priority functionalities for the platform will be ideated and refined, and a digital interactive prototype will be created. In phase 3, heuristic evaluation and three rounds of end-user testing will be conducted to ensure further refinement and usability of the prototype. In phase 4, a prospective pilot study will be performed to investigate the feasibility, acceptability, and preliminary efficacy of the developed platform over a 12-week intervention period. If HeartFIT intervention is feasible, acceptable, and demonstrates promising efficacy, an adequately powered randomized controlled trial (future work) will be deployed to test the real-world effectiveness of the intervention.

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 µM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.

p47phox-Dependent Oxidant Signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-Induced Cardiac Hypertrophy and Apoptosis.

The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.