Mechanism and use strategy of uric acid-lowering drugs on coronary heart disease.

Coronary heart disease (CHD) is a serious cardiovascular illness, for which an elevated uric acid (UA) level presents as a considerable risk factor. This can be treated with UA-lowering drugs such as allopurinol and benzbromarone, which can reduce UA levels by the inhibition of UA production or by promoting its excretion. Such drugs can also be beneficial to CHD in other ways, such as reducing the degree of coronary arteriosclerosis, improving myocardial blood supply and alleviating ventricular remodeling. Different UA-lowering drugs are used in different ways: allopurinol is preferred as a single agent in clinical application, but in absence of the desired response, a combination of drugs such as benzbromarone with ACE inhibitors may be used. Patients must be monitored regularly to adjust the medication regimen. Appropriate use of UA-lowering drugs has great significance for the prevention and treatment of CHD. However, the specific mechanisms of the drugs and individualized drug use need further research. This review article expounds the mechanisms of UA-lowering drugs on CHD and their clinical application strategy, thereby providing a reference for further optimization of treatment.

Coordinated responses of rice (Oryza sativa) to the stresses of benzotriazole ultraviolet stabilizers (BZT-UVs): Antioxidative system, photosynthetic activity, and metabolic regulation.

Massive use of plastic products has caused their accumulation in soils, releasing large amounts of endogenous plastic additives (e.g., benzotriazole ultraviolet stabilizers, in short BZT-UVs) into terrestrial ecosystems. However, their plant toxicity is little known. Herein, we investigated the occurrence of BZT-UVs in contaminated farmland and selected three BZT-UV congeners to explore their toxic effects on the antioxidant, photosynthetic, and metabolic perturbation on rice (Oryza sativa). Results showed that the mean concentrations of ∑BZT-UVs in soil and plant samples were 180.7 ng/g dw and 156.4 ng/g dw, respectively. UV-P, UV-327 and UV-328 were the dominant BZT-UV congeners in both of soils and plants. Three BZT-UV congeners caused oxidative damages to rice in a dose-dependent manner, especially for UV-328. Functional genes involved in chlorophyll synthetases was inhibited by over 50 % under the stress of BZT-UVs, whereas those responsible for chlorophyll degradation were obviously promoted. The chlorophyll content was thus decreased, leading to a weakened photosynthesis system and an unbalanced carbon metabolism. The transcriptome and metabolome proved that the flux of carbohydrate metabolism and amino acid metabolism were obviously promoted in plants induced by BZT-UVs, which could inhibit the growth of rice. These findings offered insights into the coordinated responses of plants and advanced our understanding of potential ecological risks of BZT-UVs to terrestrial ecosystems.

High-performance colorimetric sensor based on PtRu bimetallic nanozyme for xanthine analysis.

The identification and quantification of xanthine are crucial for assessing the freshness and quality of food products, particularly in the seafood industry. Herein, a new approach was developed, involving the in-situ controllable growth of Pt91Ru9 nanoparticles on graphitic carbon nitride to yield Pt91Ru9@C3N4 catalytic materials. By integrating Pt91Ru9@C3N4 with the xanthine/xanthine oxidase (XOD) enzyme catalytic system, a nanozyme-enzyme tandem platform was obtained for the quantification analysis of xanthine. Under the catalytic oxidation of xanthine by XOD in the presence O2, H2O2 was generated. Upon the addition of peroxidase-like activity of Pt91Ru9@C3N4, H2O2 can be decomposed into •OH and 1O2, which can further catalyze the oxidation of TMB to its oxidation product oxTMB with an absorption peak at 652 nm. This smartphone-assisted portable colorimetric sensor for visual monitoring xanthine with a low detection limit of 8.92 nmol L-1, and successfully applied to detect xanthine in grass carp and serum samples.

The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway.

The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.

Ratio-fluorescence sensor based on carbon dots and PtRu/CN nanozyme for efficient detection of melatonin in tablet.

The identification and quantification of melatonin (MT) are crucial for early diagnosis of disorders associated with circadian rhythm disruption. Herein, novel blue-emissive carbon dots (BCDs) were synthesized through an improved hydrothermal treatment using serine and malic acid as reductant and carbon source. The excellent optical properties of the as-obtained BCDs were used for ratiometric sensing by strategically constructing a MT sensing system integrating BCDs with C3N4 nanosheets loaded with platinum/ruthenium nanoparticles (PtRu/CN). In this system, H2O2 activated the peroxidase-like activity of PtRu/CN to generate •OH and 1O2 for oxidizing the colorless o-phenylenediamine (OPD) into yellow 2,3-diaminophenazine (DAP) with fluorescence emission at 565 nm. Concurrently, the fluorescence emission of BCDs at 439 nm was quenched by the generated DAP via the static quenching and inner filter effect (IFE) process. However, MT rapidly scavenged the generated free radicals to reverse the ratio fluorescence signal. The developed BCDs/PtRu/CN/OPD/H2O2 sensing platform enabled quantitative analysis of MT at concentrations ranging from 0.06 to 600 µmol/L with a low detection limit of 23.56 nmol/L. Moreover, smartphone-based RGB sensing of MT was successfully developed for rapid visualization and portable processing. More broadly, novel insights into the preparation of carbon dots with sensitive fluorescence sensing properties were presented, promising for future considerations.

Nanocluster-agminated amorphous cobalt nanofilms for highly selective electroreduction of nitrate to ammonia.

Developing highly-efficient electrocatalysts for the nitrate reduction reaction (NITRR) is a persistent challenge. Here, we present the successful synthesis of 14 amorphous/low crystallinity metal nanofilms on three-dimensional carbon fibers (M-NFs/CP), including Al, Ti, Mn, Fe, Co, Ni, Cu, Zn, Ag, In, Sn, Pb, Au, or Bi, using rapid thermal evaporation. Among these samples, our study identifies the amorphous Co nanofilm with fine agglomerated Co clusters as the optimal electrocatalyst for NITRR in a neutral medium. The resulting Co-NFs/CP exhibits a remarkable Faradaic efficiency (FENH3) of 91.15 % at - 0.9 V vs RHE, surpassing commercial Co foil (39 %) and Co powder (20 %), despite sharing the same metal composition. Furthermore, during the electrochemical NITRR, the key intermediates on the surface of the Co-NFs/CP catalyst were detected by in situ Fourier-transform infrared (FTIR) spectroscopy, and the possible reaction ways were probed by Density functional theory (DFT) calculations. Theoretical calculations illustrate that the abundant low-coordinate Co atoms of Co-NFs/CP could enhances the adsorption of *NO3 intermediates compared to crystalline Co. Additionally, the amorphous Co structure lowers the energy barrier for the rate-determining step (*NH2→*NH3). This work opens a new avenue for the controllable synthesis of amorphous/low crystallinity metal nano-catalysts for various electrocatalysis reaction applications.

The first report and biological characterization of Avian Orthoavulavirus 16 in wild migratory waterfowl and domestic poultry in China reveal a potential threat to birds.

RESEARCH HIGHLIGHTS: First confirmation of AOAV-16 in domestic and wild birds in China.AOAV-16 are low virulent viruses for chickens.Co-circulation/co-infection of AOAV-16 and H9N2 subtype AIV enhanced pathogenicity.Different intergenic sequences and recombination events exist within AOAV-16.

Venous thromboembolism swine model with reflux-induced venous hypertension.

Objective: This study describes a novel swine model of venous thromboembolism (VTE) with reflux-induced venous hypertension. Methods: Six pigs underwent disruption of the tricuspid chordae tendineae to create reflux and venous hypertension in the femoral vein. The vein was traumatized 2 to 3 weeks later by repeated withdrawal of a slightly overinflated occlusion balloon across the lumen, followed by balloon occlusion of the outflow. A small amount of thrombin was injected into the traumatized vein segment immediately after outflow occlusion. Thrombosis of the traumatized vein evolved into an organized thrombus seven weeks later. The histological features of the harvested post-thrombotic femoral vein were studied with hematoxylin and eosin and Trichrome stains. Results: In all six pigs, initial disruption of the chordae tendineae was successfully performed to create tricuspid reflux and venous hypertension. After two-stage sequential procedures, a thrombus formed in the target femoral vein segment. Histology of the harvested thrombotic vein showed features of an organizing thrombus with collagen formation and fibrosis. Conclusions: The novel swine VTE model may serve as a platform for developing and testing human-sized therapeutic procedures and devices in translational venous research. Clinical Relevance: This study describes a swine model of VTE created by incorporating all three elements of Virchow's triad. The model uniquely incorporates reflux-induced venous hypertension, which may be used in studying venous insufficiency and VTE in those with systemic venous hypertension. Likewise, this model may serve as a platform for development and evaluation of diagnostic imaging or therapeutic procedures and devices in subjects with systemic venous hypertension.

Long Non-Coding RNA Analysis: Severe Pathogenicity in Chicken Embryonic Visceral Tissues Infected with Highly Virulent Newcastle Disease Virus-A Comparison to the Avirulent Vaccine Virus.

There are significant variations in pathogenicity among different virulent strains of the Newcastle disease virus (NDV). Virulent NDV typically induces severe pathological changes and high mortality rates in infected birds, while avirulent NDV usually results in asymptomatic infection. Currently, the understanding of the specific mechanisms underlying the differences in host pathological responses and symptoms caused by various virulent NDV strains remains limited. Long non-coding RNA (lncRNA) can participate in a range of biological processes and plays a crucial role in viral infection and replication. Therefore, this study employed RNA-Seq to investigate the transcriptional profiles of chicken embryos' visceral tissues (CEVTs) infected with either the virulent NA-1 strain or avirulent LaSota strain at 24 hpi and 36 hpi. Using bioinformatic methods, we obtained a total of 2532 lncRNAs, of which there were 52 and 85 differentially expressed lncRNAs at 24 hpi and 36 hpi, respectively. LncRNA analysis revealed that the severe pathological changes and symptoms induced by virulent NDV infection may be partially attributed to related target genes, regulated by differentially expressed lncRNAs such as MSTRG.1545.5, MSTRG.14601.6, MSTRG.7150.1, and MSTRG.4481.1. Taken together, these findings suggest that virulent NDV infection exploits the host's metabolic resources and exerts an influence on the host's metabolic processes, accompanied by excessive activation of the immune response. This impacts the growth and development of each system of CEVTs, breaches the blood-brain barrier, inflicts severe damage on the nervous system, and induces significant lesions. These observations may be attributed to variations in pathology. Consequently, novel insights were obtained into the intricate regulatory mechanisms governing NDV and host interactions. This will aid in unraveling the molecular mechanisms underlying both virulent and avirulent forms of NDV infection.

Review on strategies for improving the added value and expanding the scope of CO2 electroreduction products.

The electrochemical reduction of CO2 into value-added chemicals has been explored as a promising solution to realize carbon neutrality and inhibit global warming. This involves utilizing the electrochemical CO2 reduction reaction (CO2RR) to produce a variety of single-carbon (C1) and multi-carbon (C2+) products. Additionally, the electrolyte solution in the CO2RR system can be enriched with nitrogen sources (such as NO3-, NO2-, N2, or NO) to enable the synthesis of organonitrogen compounds via C-N coupling reactions. However, the electrochemical conversion of CO2 into valuable chemicals still faces challenges in terms of low product yield, poor faradaic efficiency (FE), and unclear understanding of the reaction mechanism. This review summarizes the promising strategies aimed at achieving selective production of diverse carbon-containing products, including CO, formate, hydrocarbons, alcohols, and organonitrogen compounds. These approaches involve the rational design of electrocatalysts and the construction of coupled electrocatalytic reaction systems. Moreover, this review presents the underlying reaction mechanisms, identifies the existing challenges, and highlights the prospects of the electrosynthesis processes. The aim is to offer valuable insights and guidance for future research on the electrocatalytic conversion of CO2 into carbon-containing products of enhanced value-added potential.

The effects of tranexamic acid in patients treated with extracorporeal membrane oxygenation after cardiac surgery.

BACKGROUND: The lysine analog tranexamic acid (TXA) is used as a blood protective drug in cardiac surgery, but efficacy and safety outcomes in patients treated with extracorporeal membrane oxygenation (ECMO) after surgery remain poorly understood. METHODS: From January 1, 2017 to December 31, 2022, we retrospectively analyzed patients assisted by ECMO after cardiac surgery and divided them into TXA and control groups depending on whether TXA was used or not. The primary study outcome was red blood cell (RBC) transfusion during ECMO. RESULTS: In total, 321 patients treated with ECMO after cardiac surgery were assessed; 185 patients were eligible for inclusion into to the TXA-intervention group and 136 into to the control group. RBC transfusion during ECMO was 8.0 IU (4.0 IU-14.0 IU) in the TXA group versus 10.0 IU (6.0 IU-16.0 IU) in the control group (p = .034). Median total chest drainage volume after surgery was 1460.0 mL (650.0-2910.0 mL) and 1680.0 mL (900.0-3340.0 mL) in TXA and control groups, respectively (p = .021). Postoperative serum D-dimer levels were significantly lower in the TXA group when compared with the control group; 1.125 µg/mL (0.515-2.176 µg/mL) versus 3.000 µg/mL (1.269-5.862 µg/mL), p < .001. Serious adverse events, including vascular occlusive events, did not differ meaningfully between groups. CONCLUSIONS: In patients treated with ECMO after cardiac surgery, TXA infusion modestly but significantly reduced RBC transfusions and chest tube output when compared with the control group.

One-Step Prepared Multifunctional Polyacrylonitrile/MIL-100(Fe) Membrane with High-Density Porous Fibers for Efficient Dye/Oil Wastewater Remediation.

With environmental pollution becoming more serious, developing efficient treatment technologies for all kinds of organic wastewater has become the focus of current research. In this work, the coaxial electrospinning technology was used to one-step fabricate a porous and underwater superoleophobic polyacrylonitrile nanofibrous membrane with an Fe-based metal-organic framework (MIL-100(Fe)). Benefiting from the synergistic effect of two jets, the nanofibers are smaller and denser, which prompt the exposure of more nanomaterial additives (MIL-100(Fe)). The BET surface area increased to 202.888 m2/g, and the membranes demonstrated outstanding underwater superoleophobicity. Moreover, compared with traditional blended matrix membranes by the single-axis method, separation of the modifier and membrane matrix material by coaxial methods also maintained excellent mechanical properties, which enhanced Young's modulus 3.4 times (∼1.34 MPa). As a result, facing soluble dyes, the porous C-PAN/MIL-100(Fe) membrane can demonstrate outstanding and fast adsorptive property (the Qm of MB and CR reached 44.71 and 88.74 mg g-1, respectively). For oily emulsion, the hydrophilic and oleophobic nanofibrous reticular surface provided excellent separation performance (flux: 1124.0-1549.3 L m-2 h-1, R > 98%). Moreover, the porous and underwater superoleophobic C-PAN/MIL-100(Fe)-0.5 membrane can synchronously purify the dye/oil mixture emulsions by one-step filtration. Based on the above performance, we believe that the modified nanofibrous membrane prepared by one-step coaxial electrospinning technology can promote more studies of the development of membrane preparation technology in the field of oily wastewater treatment.

Photoaged microplastics enhanced the antibiotic resistance dissemination in WWTPs by altering the adsorption behavior of antibiotic resistance plasmids.

Growing concerns have raised about the microplastic eco-coronas in the ultraviolet (UV) disinfection wastewater, which accelerated the pollution of antibiotic resistance genes (ARGs) in the aquatic environment. As the hotspot of gene exchange, microplastics (MPs), especially for the UV-aged MPs, could alter the spread of ARGs in the eco-coronas and affect the resistance of the environment through adsorbing antibiotic resistant plasmids (ARPs). However, the relationship between the MP adsorption for ARPs and ARG spreading characteristics in MP eco-corona remain unclear. Herein, this study explored the distribution of ARGs in the MP eco-corona through in situ investigations of the discharged wastewater, and the adsorption behaviors of MPs for ARPs by in vitro adsorption experiments and in silico calculations. Results showed that the adsorption capacity of MPs for ARPs was enhanced by 42.7-48.0 % and the adsorption behavior changed from monolayer to multilayer adsorption after UV-aging. It was related to the increased surface roughness and oxygen-containing functional groups of MPs under UV treatment. Moreover, the abundance of ARGs in MP eco-corona of UV-treated wastewater was 1.33-1.55 folds higher than that without UV treatment, promoting the proliferation of drug resistance. DFT and DLVO theoretical calculations indicated that the MP-ARP interactions were dominated by electrostatic physical adsorption, endowing the aged MPs with low potential oxygen-containing groups to increase the electrostatic interaction with ARPs. Besides, due to the desorption of ARPs on MPs driven by the electrostatic repulsion, the bioavailability of ARGs in the MP eco-coronas was increased with pH and decreased with salinity after the wastewater discharge. Overall, this study advanced the understanding of the adsorption behavior of MPs for ARPs and provided inspirations for the evaluation of the resistance spread in the aquatic environment mediated by MP eco-coronas.

SERS Immunoassay Based on an Enzyme-Catalyzed Cascade Reaction and Metal-Organic Framework/Alkaline Phosphatase for Ultrasensitive Detection of Adenosine Triphosphate.

Herein, an adenosine triphosphate (ATP)-induced enzyme-catalyzed cascade reaction system based on metal-organic framework/alkaline phosphatase (MOF/ALP) nanocomposites was designed to establish a surface-enhanced Raman spectroscopy (SERS) biosensor for use in rapid, sensitive ATP detection. Numerous ALP molecules were first encapsulated using ZIF-90 to temporarily deactivate the enzyme activity, similar to a lock. Au nanostars (AuNSs), as SERS-enhancing substrates, were combined with o-phenylenediamine (OPD) to form AuNSs@OPD, which could significantly improve the Raman signal of OPD. When the target ATP interacted with the MOF/ALP nanocomposites, ATP could act as a key to open the MOF structure, releasing ALP, which should further catalyze the conversion of OPD to oxOPD with the aid of ascorbic acid 2-phosphate. Therefore, with the increasing concentrations of ATP, more ALP was released to catalyze the conversion of OPD, resulting in the reduced intensity of the Raman peak at 1262 cm-1, corresponding to the level of OPD. Based on this principle, the ATP-induced enzyme-catalyzed cascade reaction SERS biosensor enabled the ultrasensitive detection of ATP, with a low detection limit of 0.075 pM. Consequently, this study provides a novel strategy for use in the ultrasensitive, rapid detection of ATP, which displays considerable potential for application in the fields of biomedicine and disease diagnosis.

Expression and identification of recombinant adenovirus type 5-Norovirus GⅡ.4-VP1 virus-like particles / 中国生物制品学杂志

@#Objective To express and identify recombinant adenovirus type 5-Norovirus(NoV)GⅡ.4-VP1 virus-like particles(VLPs)in 293T cells. Methods The recombinant adenovirus plasmids pAd5-eGFP and pAd5-NoV-GⅡ.4-VP1 were transfected into 293T cells respectively,and the recombinant adenovirus rAd5-eGFP and rAd5-NoV-GⅡ.4-VP1 were rescued. The rAd5-eGFP was subcultured in 293T cells to verify the function of the vector. The rAd5-NoV-GⅡ.4-VP1 was subcultured in293T cells,expressed and purified,and then NoV-GⅡ.4-VLP was formed by self-assembly,which was detected by Western blot,ELISA and observed by transmission electron microscope. Results The green fluorescence of the recombinant adenovirus rAd5-eGFP of various generations was observed under microscope,and the brightness increased with the increase of generations. NoV-GⅡ.4-VP1 protein was expressed in the harvested solution of recombinant adenovirus rAd5-NoV-GⅡ.4-VP1 of various generations,with a relative molecular mass of about 58 900. NoV-GⅡ.4-VLP showed specific binding to the rabbit anti-NoV-GⅡ.4-VP1 serum;it had similar conformation to natural NoV virus particles and can effectively identify NoV receptors in volunteer saliva samples;microscopic observation showed that the morphology was complete and spherical,with a diameter of 43. 5 — 58. 3 nm,while there were a few protrusions on the surface of the particles,which might be the P domain exposedon the particle surface during self-assembly of VP1. Conclusion The expressed recombinant adenovirus NoV-GⅡ. 4-VLP has complete VLP structure and good specificity,and is expected to be used in the related research of NoV adenovirus vector vaccine.

Novel venous balloon for compliance measurement and stent sizing in a post-thrombotic swine model.

Objective: Real-time accurate venous lesion characterization is needed during endovenous interventions for stent deployment. The goal of this study is to validate a novel device for venoplasty sizing and compliance measurements. Methods: A compliance measuring sizing balloon (CMSB) uses real-time electrical conductance measurements based on Ohm's Law to measure the venous size and compliance in conjunction with pressure measurement. The sizing accuracy and repeatability of the CMSB system were performed with phantoms on the bench and in a swine model with an induced post thrombotic (PT) stenosis in the common femoral vein of swine. Results: The accuracy and repeatability of the CMSB system were validated with phantom bench studies of known dimensions in the range of venous diameters. In 9 swine (6 experimental and 3 control animals), the luminal cross-sectional areas (CSA) increased heterogeneously along the PT stenosis when the CMSB system was inflated by stepwise pressures. The PT stenosis showed lower compliance compared to the non-PT vein segments (5 mm2 vs. 10 mm2 and 13 mm2 at a pressure change of 40 cm H2O). Compliance had no statistical difference between venous hypertension (VHT) and Control. Compliance at PT stenosis, however, was significantly smaller than that at Control and VHT (p < 0.05, ANOVA). Conclusion: The CMSB system provides accurate, repeatable, real-time measurements of CSA and compliance for assessment of venous lesions to guide interventions. These findings provide the impetus for future first-in-human studies.

Bufalin targeting CAMKK2 inhibits the occurrence and development of intrahepatic cholangiocarcinoma through Wnt/ß-catenin signal pathway.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) accounts for about 15% of primary liver cancer, and the incidence rate has been rising in recent years. Surgical resection is the best treatment for ICC, but the 5-year survival rate is less than 30%. ICC signature genes are crucial for the early diagnosis of ICC, so it is especially important to find its signature genes and therapeutic drug. Here, we studied that bufalin targeting CAMKK2 promotes mitochondrial dysfunction and inhibits the occurrence and metastasis of intrahepatic cholangiocarcinoma through Wnt/ß-catenin signal pathway. METHODS: IC50 of bufalin in ICC cells was determined by CCK8 and invasive and migratory abilities were verified by wound healing, cell cloning, transwell and Western blot. IF and IHC verified the expression of CAMKK2 between ICC patients and normal subjects. BLI and pull-down demonstrated the binding ability of bufalin and CAMKK2. Bioinformatics predicted whether CAMKK2 was related to the Wnt/ß-catenin pathway. SKL2001, an activator of ß-catenin, verified whether bufalin acted through this pathway. In vitro and in vivo experiments verified whether overexpression of CAMKK2 affects the proliferative and migratory effects of ICC. Transmission electron microscopy verified mitochondrial integrity. Associated Ca2+ levels verified the biological effects of ANXA2 on ICC. RESULTS: It was found that bufalin inhibited the proliferation and migration of ICC, and CAMKK2 was highly expressed in ICC, and its high expression was positively correlated with poor prognosis.CAMKK2 is a direct target of bufalin, and is associated with the Wnt/ß-catenin signaling pathway, which was dose-dependently decreased after bufalin treatment. In vitro and in vivo experiments verified that CAMKK2 overexpression promoted ICC proliferation and migration, and bufalin reversed this effect. CAMKK2 was associated with Ca2+, and changes in Ca2+ content induced changes in the protein content of ANXA2, which was dose-dependently decreasing in cytoplasmic ANXA2 and dose-dependently increasing in mitochondrial ANXA2 after bufalin treatment. In CAMKK2 overexpressing cells, ANXA2 was knocked down, and we found that reversal of CAMKK2 overexpression-induced enhancement of ICC proliferation and migration after siANXA2. CONCLUSIONS: Our results suggest that bufalin targeting CAMKK2 promotes mitochondrial dysfunction and inhibits the proliferation and migration of intrahepatic cholangiocarcinoma through Wnt/ß-catenin signal pathway. Thus, bufalin, as a drug, may also be used for cancer therapy in ICC in the future.

Experimental study and numerical analysis on axial compression of round-ended concrete filled CFRP-aluminum tube columns.

To enhance the concrete confinement ability of circular-ended aluminum alloy tubes, carbon fiber reinforced polymer (CFRP) was bonded onto the tube surface to form CFRP confined concrete columns with circular ends (RCFCAT). Eight specimens were designed with number of CFRP layers and section aspect ratio as variables. Axial loading test and finite element analysis were carried out. Results showed CFRP delayed buckling of the aluminum alloy tube flat surfaces, transforming inclined shear buckling failure into CFRP fracture failure. Specimens with aspect ratio above 4 experienced instability failures. Under same cross-section, CFRP increased axial compression bearing capacity and ductility by up to 30.8% and 43.4% respectively. As aspect ratio increased, enhancement coefficients of bearing capacity and ductility gradually decreased, the aspect ratio is restrictive when it is less than 2.5. CFRP strengthening increased initial axial compression stiffness of specimens by up to 117.9%. The stiffness decreased gradually with increasing aspect ratio, with most significant increase at aspect ratio of 4. Strain analysis showed CFRP bonding remarkably reduced circumferential and longitudinal strains. Confinement effect was optimal at aspect ratio around 2.0. The rationality of the refined FE model established has been verified in terms of load displacement curves, capturing circular aluminum tube oblique shear buckling, concrete "V" shaped crushing, and CFRP tearing during specimen failure. The parameter analysis showed that increasing the number of CFRP layers is one of the most effective methods for improving the ultimate bearing capacity of RCFCAT.

Camouflaged Nanoreactors Mediated Radiotherapy-Adjuvant Chemodynamic Synergistic Therapy.

Chemodynamic therapy based on the Fenton-like catalysis ability of Fe3O4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe3O4@HfO2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe3O4 and a radiosensitizer HfO2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO2-Fe3O4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.