Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose.

Activation of extracellular matrix-producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)-, carbon tetrachloride (CCl4)-, or bile duct ligation (BDL)-induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.

The Particle Drifting Effect: A Combined Function of Colloidal and Drug Properties.

The particle drifting effect, where nanosized colloidal drug particles overcome the diffusional resistance of the aqueous boundary layer adjacent to the intestinal wall and increase drug absorption rates, is drawing increasing attention in pharmaceutical research. However, mechanistic understanding and accurate prediction of the particle drifting effect remain lacking. In this study, we systematically evaluated the extent of the particle drifting effect affected by drug and colloidal properties, including the size, number, and type of the moving species using biphasic diffusion experiments combined with computational fluid dynamics simulations and mass transport analyses. The results showed that the particle drifting effect is a sequential reaction of particle dissolution/dissociation in the diffusional boundary layer, followed by absorption of the free drug. Therefore, factors affecting the rate-limiting step, which can be either process or both under different circumstances, alter the particle drifting effect. Experimental results also agree with the theory that the particle dissolution rate is dependent on particle size, concentration, and drug solubility. In addition, rapid bile micelle dissociation and bile salt absorption facilitated drug absorption by the particle drifting effect. Our findings explain the highly dynamic nature of the particle drifting effect and will contribute to rational formulation development and better bioavailability prediction for formulations containing colloidal particles.

Dual LSPR and CT synergy: 3D urchin-like Au@W18O49 enables highly sensitive in-situ SERS detection of dissolved furfural in insulating oils.

Assessing the levels of furfural in insulating oils is a crucial technical method for evaluating the degree of aging and mechanical deterioration of oil-paper insulation. The surface-enhanced Raman spectroscopy (SERS) technique provides an effective method for enhancing the sensitivity of in-situ detection of furfural. In this study, a homogeneous three-dimensional (3D) urchin-like Au@W18O49 heterostructure was synthesized as a SERS substrate using a straightforward hydrothermal method. The origin of the superior Raman enhancement properties of the 3D urchin-like heterostructures formed by the noble metal Au and the plasmonic semiconductor W18O49, which is rich in oxygen vacancies, is analyzed experimentally in conjunction with density-functional theory (DFT) calculations. The Raman enhancement is further amplified by the remarkable dual localized surface plasmon resonance (LSPR) effect, which generates a strong local electric field and creates numerous "hot spots," in addition to the interfacial charge transport (CT). The synergistic effect of these factors results in the 3D urchin-like Au@W18O49 heterostructure exhibiting exceptionally high SERS activity. Testing the rhodamine 6G (R6G) probe resulted in a Raman enhancement factor of 3.41 × 10-8, and the substrate demonstrated excellent homogeneity and stability. Furthermore, the substrate was effectively utilized to achieve highly sensitive in-situ surface-enhanced Raman scattering (SERS) detection of dissolved furfural in complex plant insulating oils. The development of the 3D urchin-like Au@W18O49 heterostructure and the exploration of its enhancement mechanism provide theoretical insights for the advancement of high-performance SERS substrates.

Association Between Systemic Inflammation Response Index and Slow Coronary Flow Phenomenon in Patients with Ischemia and No Obstructive Coronary Arteries.

Background: Inflammation plays a key role in the pathogenesis of slow coronary flow phenomenon (SCFP). SCFP is a condition that can complicate the management of ischemia and no obstructive coronary arteries (INOCA), making it essential to identify reliable predictors. Although the systemic inflammation response index (SIRI) has been proven to relate to various cardiovascular diseases. However, the predictive value of SIRI for SCFP in patients with INOCA remains unclear. Methods: A total of 1422 patients with INOCA were consecutively included in this study. 89 individuals were diagnosed with SCFP (the SCFP group). A 1:2 age- and -sex-matched patients with INOCA and normal blood flow were selected as the control group (n=178). Plasma neutrophil, monocyte, and lymphocyte counts were collected so as to determine the value of SIRI. Results: Patients with SCFP had an elevated level of body mass index (BMI) and an increased incidence of smoking and diabetes. The SIRI was significantly higher in the SCFP group than in the controls (2.3±1.3 vs 1.8±1.3, p=0.002). The SIRI increased as the number of coronary arteries involved in the SCFP increased. Univariate analyses showed that BMI, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and SIRI were associated with SCFP. Multivariate logistic regression analysis revealed that BMI and SIRI were independent predictors of SCFP occurrence. The ROC curve showed that when the SIRI was > 1.140, the sensitivity and specificity were 87.6% and 60.1%, respectively, and the area under the ROC curve (AUC) was 0.644 (95% CI: 0.578-0.710, P < 0.001). Conclusion: The findings demonstrated that an increased SIRI may have a potential role in distinguishing SCFP in patients with INOCA. SIRI could improve the predictive value of SCFP compared to neutrophils, monocytes, and lymphocytes alone.

View-guided Cost Volume for Light Field Arbitrary-view Disparity Estimation.

Per-view disparity estimation for light field (LF) is critical for various applications such as light field editing, but previous work mostly focuses on estimating disparity for the center view. In this paper, we propose a view-guided cost volume (VGCV), which successfully generates high-quality disparity maps for LF arbitrary view. Unlike previous methods that construct a static cost for center view only, VGCV is designed with view information and can be applicable to arbitrary-view estimation. In particular, since the key to achieving it is to condition cost on view, we extend previous static cost to a conditional one by introducing the spatial and angular information of target view into cost construction and aggregation, experiments show that this way can effectively adapt VGCV to arbitrary-view task. For construction, previous stereo-matching methods usually adopt correlation (e.g., variance) for dynamic estimation, but just using correlation can lose image structure information, which is essential for scene detail recovery, therefore we design an image-guided construction module and use cross-view attention to adapt cost for conditional construction while keeping its spatial information. Then for aggregation, we present a coordinate-guided aggregation module for VGCV regularization, which is specially designed to solve the problem of LF view deviation. Finally, we implement a Light Field Arbitrary-View Disparity Estimation Network (LFAVNet), then perform it on both synthetic and real LFs. Experiments demonstrate that LFAVNet can generate a higher-quality disparity map for arbitrary view in LF. We also extend our method to center-view estimation and light field editing tasks, which all achieve advanced performance.

Global bibliometric mapping of the research trends in artificial intelligence-based digital pathology for lung cancer over the past two decades.

Background and Objective: The rapid development of computer technology has led to a revolutionary transformation in artificial intelligence (AI)-assisted healthcare. The integration of whole-slide imaging technology with AI algorithms has facilitated the development of digital pathology for lung cancer (LC). However, there is a lack of comprehensive scientometric analysis in this field. Methods: A bibliometric analysis was conducted on 197 publications related to digital pathology in LC from 502 institutions across 39 countries, published in 97 academic journals in the Web of Science Core Collection between 2004 and 2023. Results: Our analysis has identified the United States and China as the primary research nations in the field of digital pathology in LC. However, it is important to note that the current research primarily consists of independent studies among countries, emphasizing the necessity of strengthening academic collaboration and data sharing between nations. The current focus and challenge of research related to digital pathology in LC lie in enhancing the accuracy of classification and prediction through improved deep learning algorithms. The integration of multi-omics studies presents a promising future research direction. Additionally, researchers are increasingly exploring the application of digital pathology in immunotherapy for LC patients. Conclusions: In conclusion, this study provides a comprehensive knowledge framework for digital pathology in LC, highlighting research trends, hotspots, and gaps in this field. It also provides a theoretical basis for the application of AI in clinical decision-making for LC patients.

Growth Mechanisms of Amorphous Nanoparticles in Solution and During Heat Drying.

The purpose of this study was twofold: to identify the growth mechanisms of amorphous nanoparticles in solution and during the drying process at high temperatures, and to guide the process condition and stabilizer selection for amorphous nanoparticle formulations. In contrast to nanocrystals that are mostly mechanically robust, amorphous nanoparticles tend to undergo deformation under stress. As a result, development of a stable formulation and evaluation of the drying process for re-dispersible amorphous nanoparticles present considerable challenges. Although amorphous nanoparticles have stability issues, they have several pros in terms of production, high monodispersity, and diverse applications in drug delivery. In this study, amorphous nanoparticles were prepared via liquid-liquid phase separation, and their growth mechanisms were investigated both in solution and during the drying process. In solution, particles were found to be susceptible to flocculation, crystallization, coalescence, and Ostwald ripening, with coalescence being a preliminary step providing the driving force for Ostwald ripening. However, during the heat drying process, coalescence and crystallization were found to be the primary mechanisms for particle growth, with Ostwald ripening being negligible due to reduced molecular mobility. The glass transition temperature (Tg) of these amorphous nanoparticles was found to be a crucial factor both in solution and during the drying process. At temperatures < Tg, particles remained in a rigid, glassy state thereby inhibiting coalescence, whereas at or above Tg, particles transition from glassy to rubbery state, making them more susceptible to deformation and coalescence. The mechanistic understanding of particle growth from this study can also be extended to the stabilization of other types of soft nanoparticles.

Plasma ofCS-modified CD44 predicts the survival of patients with lung cancer.

Plasma levels of oncofetal chondroitin sulfate (ofCS)-modified CD44 have emerged as a promising biomarker for multi-cancer detection. Here, we explored its potential to predict the survival of patients with lung cancer. A prospective observational cohort was conducted involving 274 newly diagnosed patients with lung cancer at the Sun Yat-sen University Cancer Center from 2013 to 2015. The plasma levels of ofCS-modified CD44 were measured, and Cox regression analysis was performed to assess the association between plasma-modified CD44 levels and overall survival (OS) as well as other prognostic outcomes. Prognostic nomograms were constructed based on plasma ofCS-modified CD44 levels to predict survival outcomes for patients with lung cancer. Patients with high expression ofCS-modified CD44 exhibited significantly worse outcomes in terms of OS (HR = 1.61, 95%CI = 1.13-2.29, p = 0.009) and progression-free survival (PFS). These findings were consistent across various analyses. The concordance index of the prognostic nomogram for predicting OS in both the training set and validation set were 0.723 and 0.737, respectively. Additionally, time-dependent receiver operating characteristic (ROC) curves showed that the nomogram could serve as a useful tool for predicting OS in patients with lung cancer. Plasma ofCS-modified CD44 may serve as an independent prognosis marker for patients with lung cancer. Further validation of its predictive value could enhance prognostic assessment and guide personalized treatment strategies for patients with lung cancer.

Encapsulation of Pd Single-Atom Sites in Zeolite for Highly Efficient Semihydrogenation of Alkynes.

Palladium (Pd)-based single-atom catalysts (SACs) have shown outstanding selectivity for semihydrogenation of alkynes, but most Pd single sites coordinated with highly electronegative atoms (such as N, O, and S) of supports will result in a decrease in the electron density of Pd sites, thereby weakening the adsorption of reactants and reducing catalytic performance. Constructing a rich outer-shell electron environment of Pd single-atom sites by changing the coordination structure offers a novel opportunity to enhance the catalytic efficiency with excellent alkene selectivity. Therefore, in this work, we first propose the in situ preparation of isolated Pd sites encapsulated within Al/Si-rich ZSM-5 structure using the one-pot seed-assisted growth method. Pd1@ZSM-5 features Pd-O-Al/Si bonds, which can boost the domination of d-electron near the Fermi level, thereby promoting the adsorption of substrates on Pd sites and reducing the energy barrier for the semihydrogenation of alkynes. In semihydrogenation of phenylacetylene, Pd1@ZSM-5 catalyst performs the highest turnover frequency (TOF) value of 33582 molC═C/molPd/h with 96% selectivity of styrene among the reported heterogeneous catalysts and nearly 17-fold higher than that of the commercial Lindlar catalyst (1992 molC═C/molPd/h). This remarkable catalytic performance can be retained even after 6 cycles of usage. Particularly, the zeolitic confinement structure of Pd1@ZSM-5 enables precise shape-selective catalysis for alkyne reactants with a size less than 4.3 Å.

Prognostic Value of Insulin Growth Factor-Like Receptor 1 (IGFLR1) in Stage II and III Colorectal Cancer and Its Association with Immune Cell Infiltration.

IGFLR1 is a novel biomarker, and some evidences suggested that is involved in the immune microenvironment of CRC. Here, we explored the expression of IGFLR1 and its association with the prognosis as well as immune cell infiltration in CRC, with the aim to provide a basis for further studies on IGFLR1. Immunohistochemical staining for IGFLR1, TIM-3, FOXP3, CD4, CD8, and PD-1 was performed in eligible tissues to analyze the expression of IGFLR1 and its association with prognosis and immune cell infiltration. Then, we screened colon cancer samples from TCGA and grouped patients according to IGFLR1-related genes. We also evaluated the co-expression and immune-related pathways of IGFLR1 to identify the potential mechanism of it in CRC. When P < 0.05, the results were considered statistically significant. IGFLR1 and IGFLR1-related genes were associated with the prognosis and immune cell infiltration (P < 0.05). In stage II and III CRC tissue and normal tissue, we found (1) IGFLR1 was expressed in both the cell membrane and cytoplasm and which was differentially expressed between cancer tissue and normal tissue. IGFLR1 expression was associated with the expression of FOXP3, CD8, and gender but was not associated with microsatellite instability. (2) IGFLR1 was an independent prognostic factor and patients with high IGFLR1 had a better prognosis. (3) A model including IGFLR1, FOXP3, PD-1, and CD4 showed good prognostic stratification ability. (4) There was a significant interaction between IGFLR1 and GATA3, and IGFLR1 had a significant co-expression with related factors in the INFR pathway. IGFLR1 has emerged as a new molecule related to disease prognosis and immune cell infiltration in CRC patients and showed a good ability to predict the prognosis of patients.

Amaranth Plants with Various Color Phenotypes Recruit Different Soil Microorganisms in the Rhizosphere.

To explore and utilize the abundant soil microorganisms and their beneficial functions, high-throughput sequencing technology was used to analyze soil microbial compositions in the rhizosphere of red and green amaranth varieties. The results showed that significant differences in soil microbial composition could be found in the rhizosphere of amaranth plants with different color phenotypes. Firstly, soil bacterial compositions in the rhizosphere were significantly different between red and green amaranths. Among them, Streptomyces, Pseudonocardia, Pseudolabrys, Acidibacter, norank_ f_ Micropepsaceae, Bradyrhizobium, and Nocardioides were the unique dominant soil bacterial genera in the rhizosphere of red amaranth. In contrast, Conexibacter, norank_f_norank_o_norank_c_TK10, and norank_f_ norank_o_ norank_ c_AD3 were the special dominant soil bacterial genera in the rhizosphere of green amaranth. Additionally, even though the soil fungal compositions in the rhizosphere were not significantly different between red and green amaranths, the abundance of the dominant soil fungal genera in the rhizosphere showed significant differences between red and green amaranths. For example, unclassified_k__Fungi, Fusarium, Cladophialophora, unclassified_c__Sordariomycetes and unclassified_p__Chytridiomycota significantly enriched as the dominant soil fungal genera in the rhizosphere of the red amaranth. In contrast, Aspergillues only significantly enriched as the dominant soil fungal genus in the rhizosphere of green amaranth. All of the above results indicated that amaranth with various color phenotypes exactly recruited different microorganisms in rhizosphere, and the enrichments of soil microorganisms in the rhizosphere could be speculated in contributing to amaranth color formations.

Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling.

BACKGROUND: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets. METHODS: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA. RESULTS: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly. CONCLUSION: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Establishing and clinically validating a machine learning model for predicting unplanned reoperation risk in colorectal cancer.

BACKGROUND: Colorectal cancer significantly impacts global health, with unplanned reoperations post-surgery being key determinants of patient outcomes. Existing predictive models for these reoperations lack precision in integrating complex clinical data. AIM: To develop and validate a machine learning model for predicting unplanned reoperation risk in colorectal cancer patients. METHODS: Data of patients treated for colorectal cancer (n = 2044) at the First Affiliated Hospital of Wenzhou Medical University and Wenzhou Central Hospital from March 2020 to March 2022 were retrospectively collected. Patients were divided into an experimental group (n = 60) and a control group (n = 1984) according to unplanned reoperation occurrence. Patients were also divided into a training group and a validation group (7:3 ratio). We used three different machine learning methods to screen characteristic variables. A nomogram was created based on multifactor logistic regression, and the model performance was assessed using receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis. The risk scores of the two groups were calculated and compared to validate the model. RESULTS: More patients in the experimental group were ≥ 60 years old, male, and had a history of hypertension, laparotomy, and hypoproteinemia, compared to the control group. Multiple logistic regression analysis confirmed the following as independent risk factors for unplanned reoperation (P < 0.05): Prognostic Nutritional Index value, history of laparotomy, hypertension, or stroke, hypoproteinemia, age, tumor-node-metastasis staging, surgical time, gender, and American Society of Anesthesiologists classification. Receiver operating characteristic curve analysis showed that the model had good discrimination and clinical utility. CONCLUSION: This study used a machine learning approach to build a model that accurately predicts the risk of postoperative unplanned reoperation in patients with colorectal cancer, which can improve treatment decisions and prognosis.

An overview of global CME/CPD systems.

PURPOSE: Engagement in CME/CPD has a positive impact on healthcare professionals' (HCPs) knowledge, skills, and performance, and on patient outcomes, therefore it is critical to better understand the components of CME/CPD systems that foster engagement, high-quality education, and impact. METHODS: An assessment of CME/CPD systems was conducted using a mixed-methods approach that included interviews with in-country subject matter experts and qualitative and quantitative data from practicing in-country physicians. RESULTS: Results demonstrate areas of consistency in CME/CPD systems across world regions that included: types of educational providers; types of credit; educational formats; self-tracking of participation; high-degree of compliance when education is mandatory; overall satisfaction with available education; strong support for interprofessional education; and lack of alignment or evaluation of engagement in education with population health outcomes. Areas of variation included: whether engagement in education is required as a condition to practice medicine; whether regulations are uniformly applied; if mechanisms to ensure independence existed; and physician perceptions of independence. CONCLUSION: Results of this assessment maybe used by a variety of different stakeholders to assess how well country-level CME/CPD systems are meeting the needs of practicing physicians and determine what, if any, changes might need to be implemented to improve outcomes.

Atomic-Level Asymmetric Tuning of the Co1-N3P1 Catalyst for Highly Efficient N-Alkylation of Amines with Alcohols.

Despite the extensive development of non-noble metals for the N-alkylation of amines with alcohols, the exploitation of catalysts with high selectivity, activity, and stability still faces challenges. The controllable modification of single-atom sites through asymmetric coordination with a second heteroatom offers new opportunities for enhancing the intrinsic activity of transition metal single-atom catalysts. Here, we prepared the asymmetric N/P hybrid coordination of single-atom Co1-N3P1 by absorbing the Co-P complex on ZIF-8 using a concise impregnation-pyrolysis process. The catalyst exhibits ultrahigh activity and selectivity in the N-alkylation of aniline and benzyl alcohol, achieving a turnover number (TON) value of 3480 and a turnover frequency (TOF) value of 174-h. The TON value is 1 order of magnitude higher than the reported catalysts and even 37-fold higher than that of the homogeneous catalyst CoCl2(PPh3)2. Furthermore, the catalyst maintains its high activity and selectivity even after 6 cycles of usage. Controlling experiments and isotope labeling experiments confirm that in the asymmetric Co1-N3P1 system, the N-alkylation of aniline with benzyl alcohol proceeds via a transfer hydrogenation mechanism involving the monohydride route. Theoretical calculations prove that the superior activity of asymmetric Co1-N3P1 is attributed to the higher d-band energy level of Co sites, which leads to a more stable four-membered ring transition state and a lower reaction energy barrier compared to symmetrical Co1-N4.

CuFe2O4/lignin-based carbon composited photothermal and photodynamic agents for synergetic antibacterial therapy.

Bacterial infection has become the second leading cause of death in the world. Exploring a new highly antibacterial catalyst to replace traditional antibacterial agent is crucial for the society development of human beings. In this study, CuFe2O4/Lg-based carbon composited catalysts were rationally constructed by facile hydrothermal method. Lignin-derived carbon with enormous oxygen-containing functional group was beneficial to anchor CuFe2O4 nanoparticles. The close contact interface between CuFe2O4 and Lignin-based carbon material was expected to extend the range of optical absorption and promote the separation and transportation of photogenerated carriers. Under NIR (980 nm, 1.5 W/cm2) light irradiation, the as-prepared CuFe2O4/Lg (20 µg/mL) exhibited excellent photo/photothermal synergetic in vitro (against Escherichia coli and Staphylococcus aureus) and in vivo (against Staphylococcus aureus-infected mouse wound model) antibacterial performance. Furthermore, the cell count assay kit 8 (CCK-8 kit) demonstrated the good biocompatibility of this material. On the basis of the experimental results, a possible antibacterial mechanism based on the synergetic photothermal and photodynamic therapies was proposed. This work presented a lignin- derived carbon-based highly efficient antibacterial disinfection agent with desirable biosafety.

APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma by suppressing MEK/ERK and CREB/Bcl-xl pathways.

BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.

Lactobacillus rhamnosus GG triggers intestinal epithelium injury in zebrafish revealing host dependent beneficial effects.

Lactobacillus rhamnosus GG (LGG), the well-characterized human-derived probiotic strain, possesses excellent properties in the maintenance of intestinal homeostasis, immunoregulation and defense against gastrointestinal pathogens in mammals. Here, we demonstrate that the SpaC pilin of LGG causes intestinal epithelium injury by inducing cell pyroptosis and gut microbial dysbiosis in zebrafish. Dietary SpaC activates Caspase-3-GSDMEa pathways in the intestinal epithelium, promotes intestinal pyroptosis and increases lipopolysaccharide (LPS)-producing gut microbes in zebrafish. The increased LPS subsequently activates Gaspy2-GSDMEb pyroptosis pathway. Further analysis reveals the Caspase-3-GSDMEa pyroptosis is initiated by the species-specific recognition of SpaC by TLR4ba, which accounts for the species-specificity of the SpaC-inducing intestinal pyroptosis in zebrafish. The observed pyroptosis-driven gut injury and microbial dysbiosis by LGG in zebrafish suggest that host-specific beneficial/harmful mechanisms are critical safety issues when applying probiotics derived from other host species and need more attention.